Research Topics
| STEPHEN BENKOVICSummaryAffiliation: Pennsylvania State University Country: USA Publications
Research Grants
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Detail Information
Publications
The purinosome, a multi-protein complex involved in the de novo biosynthesis of purines in humansHong Zhao
Department of Chemistry, The Pennsylvania State University, 414 Wartik Laboratory, University Park, PA 16802, USA
Chem Commun (Camb) 49:4444-52. 2013..In particular we highlight advances made towards understanding the assembly, control and function of this protein complex and the attempts made to exploit this knowledge for drug discovery...
Protein-protein and protein-DNA interactions at the bacteriophage T4 DNA replication fork. Characterization of a fluorescently labeled DNA polymerase sliding clampD J Sexton
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
J Biol Chem 271:28045-51. 1996..Upon ATP hydrolysis, the 44/62 complex triggers a conformational change in the 45 protein that may be attributed to the clamp loading onto DNA...- Biochemistry. Enzyme motions inside and outStephen J Benkovic
Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA
Science 312:208-9. 2006 - A perspective on enzyme catalysisStephen J Benkovic
Department of Chemistry, 152 Davey Laboratory, Pennsylvania State University, University Park, PA 16802, USA
Science 301:1196-202. 2003..Such coupled networks have important implications for the origin and evolution of enzymes, as well as for protein engineering... - Identification of borinic esters as inhibitors of bacterial cell growth and bacterial methyltransferases, CcrM and MenHStephen J Benkovic
Department of Chemistry, The Pennsylvania State University, 414 Wartik Laboratory, University Park, Pennsylvania 16802, USA
J Med Chem 48:7468-76. 2005..Our data demonstrate the potential for further development of borinic esters as antibacterial agents as well as leads to explore more specific inhibitors against two essential bacterial enzymes... - Replisome-mediated DNA replicationS J Benkovic
Pennsylvania State University, Department of Chemistry, 414 Wartik Laboratory, University Park, Pennsylvania 16802, USA
Annu Rev Biochem 70:181-208. 2001.... 
Impact of distal mutations on the network of coupled motions correlated to hydride transfer in dihydrofolate reductaseKim F Wong
Department of Chemistry, Pennsylvania State University, 104 Chemistry Building, University Park, PA 16802, USA
Proc Natl Acad Sci U S A 102:6807-12. 2005....- Preorganization and protein dynamics in enzyme catalysisP T Ravi Rajagopalan
Department of Chemistry, Pennsylvania State University, University Park, 16802, USA
Chem Rec 2:24-36. 2002..The general significance of protein dynamics in understanding other biological processes is briefly discussed... - Coupling interactions of distal residues enhance dihydrofolate reductase catalysis: mutational effects on hydride transfer ratesP T Ravi Rajagopalan
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
Biochemistry 41:12618-28. 2002..Natl. Acad. Sci. U.S.A. 99, 2794-2799], the data suggest that a coupled dynamic motion of these distal residues enhances crossing of the chemical reaction barrier and imply an expanded nonstatic role for the protein fold in catalysis... - Kinetic and structural characterization of dihydrofolate reductase from Streptococcus pneumoniaeJeeyeon Lee
Department of Chemistry, 414 Wartik Laboratory, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
Biochemistry 49:195-206. 2010..Understanding the role of specific amino acids in the active site coupled with detailed structural analysis will inform us on how to better design inhibitors targeting drug-resistant pathogenic bacterial DHFRs... - Surface sites for engineering allosteric control in proteinsJeeyeon Lee
Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA
Science 322:438-42. 2008..PAS-DHFR serves as a proof of concept for engineering regulatory activities into proteins through interface design at conserved allosteric sites... - The role of enzyme dynamics and tunnelling in catalysing hydride transfer: studies of distal mutants of dihydrofolate reductaseLin Wang
Department of Chemistry, University of Iowa, Iowa City, IA 52242, USA
Philos Trans R Soc Lond B Biol Sci 361:1307-15. 2006..Apparently, the coupling of the enzyme's dynamics to the reaction coordinate was altered by the mutation, supporting the models in which dynamics of the whole protein is coupled to its catalysed chemistry... - Dynamic regulation of a metabolic multi-enzyme complex by protein kinase CK2Songon An
Department of Chemistry, Pennsylvania State University, University Park, Pennsylvania 16802, USA
J Biol Chem 285:11093-9. 2010..Collectively, we provide compelling cellular evidence that CK2-mediated pathways reversibly regulate purinosome assembly, and thus the purinosome may be one of the ultimate targets of kinase inhibitors... - Reversible compartmentalization of de novo purine biosynthetic complexes in living cellsSongon An
Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA
Science 320:103-6. 2008..Collectively, the data provide strong evidence for the formation of a multi-enzyme complex, the "purinosome," to carry out de novo purine biosynthesis in cells... - Free-energy landscape of enzyme catalysisStephen J Benkovic
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
Biochemistry 47:3317-21. 2008..Experimental and theoretical evidence is presented to support this concept... - Conformation coupled enzyme catalysis: single-molecule and transient kinetics investigation of dihydrofolate reductaseNina M Antikainen
Department of Chemistry, Pennsylvania State University, 152 Davey Laboratory, University Park, Pennsylvania 16802, USA
Biochemistry 44:16835-43. 2005..These results are correlated with other measurements related to conformation coupled catalysis... - Analysis of the DNA translocation and unwinding activities of T4 phage helicasesSenthil K Perumal
414 Wartik Laboratories, Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA
Methods 51:277-88. 2010..These methods have been successfully employed to study the functions of helicases from large superfamilies... - Microtubule-assisted mechanism for functional metabolic macromolecular complex formationSongon An
Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA
Proc Natl Acad Sci U S A 107:12872-6. 2010..Collectively, we propose a microtubule-assisted mechanism for functional purinosome formation in HeLa cells... - Interaction of dihydrofolate reductase with methotrexate: ensemble and single-molecule kineticsP T Ravi Rajagopalan
Department of Chemistry, Pennsylvania State University, 152 Davey Laboratory, University Park, PA 16802, USA
Proc Natl Acad Sci U S A 99:13481-6. 2002..Thus the mechanism of methotrexate binding to DHFR involves multiple steps and protein conformational changes... - Relating protein motion to catalysisSharon Hammes-Schiffer
Department of Chemistry, Pennsylvania State University, University Park, Pennsylvania 16802, USA
Annu Rev Biochem 75:519-41. 2006..This network is comprised of fast thermal motions that are in equilibrium as the reaction progresses along the reaction coordinate and that lead to slower equilibrium conformational changes conducive to the chemical reaction... - Effects of a distal mutation on active site chemistryLin Wang
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, USA
Biochemistry 45:1383-92. 2006.... - An alternative clamp loading pathway via the T4 clamp loader gp44/62-DNA complexZhihao Zhuang
Department of Chemistry, 414 Wartik Laboratory, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
Biochemistry 45:7976-89. 2006..The collective kinetic data allowed us to propose and evaluate a sequence of steps describing this alternative pathway for clamp loading and holoenzyme formation... - On the structural and functional modularity of glycinamide ribonucleotide formyltransferasesSeung-Goo Lee
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
Protein Sci 12:2206-14. 2003..The chimeras in general, however, are subject to temperature instability and misfolding; thus, they serve primarily as useful candidates for further rounds of optimization... - Interaction between the T4 helicase loading protein (gp59) and the DNA polymerase (gp43): unlocking of the gp59-gp43-DNA complex to initiate assembly of a fully functional replisomeJun Xi
Department of Chemistry, Pennsylvania State University, 104 Chemistry Building, University Park, Pennsylvania 16802, USA
Biochemistry 44:7747-56. 2005..We conclude that gp59 acts in a manner similar to the clamp loader to ensure proper assembly of the replisome and does not remain as a replisome component during active replication... - Dissociative properties of the proteins within the bacteriophage T4 replisomeMichael A Trakselis
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
J Biol Chem 278:49839-49. 2003..The implications of these results for RNA priming and extension during the repetitive synthesis of Okazaki fragments are discussed... - Investigation of an antibody-ligase. Evidence for strain-induced catalysisSergey N Savinov
Department of Chemistry, University of Pennsylvania, Philadelphia 19104, USA
Bioorg Med Chem Lett 13:1321-4. 2003..General mechanistic implications for de novo induced catalysis are presented... - The application of a minicircle substrate in the study of the coordinated T4 DNA replicationJingsong Yang
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
J Biol Chem 278:49828-38. 2003..This inhibition only becomes significant at later times of the reaction and may be associated with the accumulation of single-stranded DNA leading to the collapse of active replisomes... - Structural and functional modularity of proteins in the de novo purine biosynthetic pathwayHui Li
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
Protein Sci 18:881-92. 2009..Implications for understanding the role of domain swapping in protein evolution are discussed... - Synthesis and biological evaluation of alpha- and gamma-carboxamide derivatives of 10-CF3CO-DDACTHFYouhoon Chong
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Bioorg Med Chem 13:3587-92. 2005..Like 1, 2 is transported into the cell by the reduced folate carrier. Unlike 1, the functional activity of 2 is not dependent upon FPGS polyglutamylation... - Synthesis and biological evaluation of N-[4-[5-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl]-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathwayHeng Cheng
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Bioorg Med Chem 13:3593-9. 2005..coli GAR Tfase as well as recombinant human AICAR Tfase. Compound 2 exhibited modest, purine-sensitive growth inhibitory activity against the CCRF-CEM cell line (IC50 = 6.0 microM)... - Tunneling and coupled motion in the Escherichia coli dihydrofolate reductase catalysisR Steven Sikorski
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, USA
J Am Chem Soc 126:4778-9. 2004..The data also suggested environmentally coupled tunneling and commitment to catalysis on pre-steady-state isotope effects... - FamClash: a method for ranking the activity of engineered enzymesManish C Saraf
Department of Chemistry, 414 Wartik Laboratory, Pennsylvania State University, University Park, PA 16802, USA
Proc Natl Acad Sci U S A 101:4142-7. 2004..Comparisons of the predicted clash map as a function of crossover position revealed good agreement with activity data, reproducing the observed V shape and matching the location of a local peak in activity... - Network of coupled promoting motions in enzyme catalysisPratul K Agarwal
Department of Chemistry, 152 Davey Laboratory, Pennsylvania State University, University Park, PA 16802, USA
Proc Natl Acad Sci U S A 99:2794-9. 2002..This type of network has broad implications for an expanded role of the protein fold in catalysis as well as ancillaries such as the engineering of altered protein function and the action of drugs distal to the active site... - 10-(2-benzoxazolcarbonyl)-5,10-dideaza-acyclic-5,6,7,8-tetrahydrofolic acid: a potential inhibitor of GAR transformylase and AICAR transformylaseThomas H Marsilje
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Bioorg Med Chem 11:4503-9. 2003..Ketone 1 and the corresponding alcohol 13 were evaluated for inhibition of GAR Tfase and AICAR Tfase and the former was found to be a potent inhibitor of recombinant human (rh) GAR Tfase (Ki=600 nM)... - The T4 phage UvsW protein contains both DNA unwinding and strand annealing activitiesScott W Nelson
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
J Biol Chem 282:407-16. 2007..The dual activities of UvsW are well suited for the DNA repair pathways described for leading strand lesion bypass and synthesis-dependent strand annealing... - Processive and unidirectional translocation of monomeric UvsW helicase on single-stranded DNAScott W Nelson
Department of Chemistry, 414 Wartik Laboratory, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
Biochemistry 48:1036-46. 2009..The ability of UvsW to unwind DNA duplexes is likely to be mechanistically linked to its ability to processively translocate on ssDNA in a 3' to 5' unidirectional fashion... - Stepwise loading of yeast clamp revealed by ensemble and single-molecule studiesRavindra Kumar
Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA
Proc Natl Acad Sci U S A 107:19736-41. 2010..These findings redefine and deepen our understanding of the clamp-loading process and reveal that it is surprisingly one of trial and error to arrive at a heuristic solution... - IPRO: an iterative computational protein library redesign and optimization procedureManish C Saraf
Department of Chemical Engineering, The Pennsylvania State University, University Park, PA 16802, USA
Biophys J 90:4167-80. 2006..Computational results demonstrate that it is indeed feasible to improve the overall library quality as exemplified by binding energy scores through targeted mutations in the parental sequences... - Investigation of stoichiometry of T4 bacteriophage helicase loader protein (gp59)Sri Ranjini Arumugam
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
J Biol Chem 284:29283-9. 2009..In addition, the presence of gp32 and gp41 proteins increases the stability of the gp59 complex, emphasizing their functional role in T4 DNA replication machinery... - Protein-protein interactions in the bacteriophage T4 replisome. The leading strand holoenzyme is physically linked to the lagging strand holoenzyme and the primosomeFaoud T Ishmael
Department of Biochemistry and Molecular Biology, Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania 17033, USA
J Biol Chem 278:3145-52. 2003..gp61.gp41 primosome complex. The resultant species is a complex of proteins that may allow coordinated leading and lagging strand synthesis, helicase DNA unwinding activity, and polymerase nucleotide incorporation... - Coordinated effects of distal mutations on environmentally coupled tunneling in dihydrofolate reductaseLin Wang
Department of Chemistry, University of Iowa, Iowa City, IA 52242, USA
Proc Natl Acad Sci U S A 103:15753-8. 2006..This observation is in accordance with the notion that these remote residues are part of a dynamic network that is coupled to the catalyzed chemistry... - Repetitive lagging strand DNA synthesis by the bacteriophage T4 replisomeMichelle M Spiering
Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA
Mol Biosyst 4:1070-4. 2008.... - Discovery of antibacterial cyclic peptides that inhibit the ClpXP proteaseLin Cheng
Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
Protein Sci 16:1535-42. 2007..The screen used here could be adapted to identify cyclic peptide inhibitors of any enzyme that can be expressed in E. coli in conjunction with a fluorescent reporter... - Site-directed mutations of T4 helicase loading protein (gp59) reveal multiple modes of DNA polymerase inhibition and the mechanism of unlocking by gp41 helicaseScott W Nelson
Department of Chemistry, Pennsylvania State University, University Park, Pennsylvania 16802, USA
J Biol Chem 281:8697-706. 2006.... - The control mechanism for lagging strand polymerase recycling during bacteriophage T4 DNA replicationJingsong Yang
Department of Chemistry, 414 Wartik Laboratory, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
Mol Cell 21:153-64. 2006..We formulate a signaling model capable of rationalizing the distribution of Okazaki fragments under various conditions for this and possibly other replisomes... - Examination of the role of the clamp-loader and ATP hydrolysis in the formation of the bacteriophage T4 polymerase holoenzymeMichael A Trakselis
Department of Chemistry, 415 Wartik Laboratory, The Pennsylvania State University, University Park, PA 16802, USA
J Mol Biol 326:435-51. 2003..Although this sequential assembly mechanism can be generally applied to most other replication systems studied to date, the specifics of ATP utilization seem to vary across replication systems... - 10-Formyl-5,10-dideaza-acyclic-5,6,7,8-tetrahydrofolic acid (10-formyl-DDACTHF): a potent cytotoxic agent acting by selective inhibition of human GAR Tfase and the de novo purine biosynthetic pathwayThomas H Marsilje
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Bioorg Med Chem 10:2739-49. 2002..coli enzyme (K(i) for 3, 14nM against rhGAR Tfase versus 6 microM against E. coli GAR Tfase) which also accounts for their exceptional cytotoxic potency... - Interaction between the T4 helicase-loading protein (gp59) and the DNA polymerase (gp43): a locking mechanism to delay replication during replisome assemblyJun Xi
Department of Chemistry, Pennsylvania State University, 104 Chemistry Building, University Park, Pennsylvania 16802, USA
Biochemistry 44:2305-18. 2005..Thus, continued assembly of the replisome through addition of the primosome components and elements of the lagging-strand holoenzyme can occur without leading-strand DNA replication... - Genetically selected cyclic-peptide inhibitors of AICAR transformylase homodimerizationAli Tavassoli
Department of Chemistry, Pennsylvania State University, University Park, 16802, USA
Angew Chem Int Ed Engl 44:2760-3. 2005 - Design, synthesis and biological evaluation of 10-CF3CO-DDACTHF analogues and derivatives as inhibitors of GAR Tfase and the de novo purine biosynthetic pathwayJoel Desharnais
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Bioorg Med Chem 11:4511-21. 2003..120 microM) and very selective (> or =100-fold) for rh versus E. coli GAR Tfase. Additional key analogues of 1 were examined (7 and 8) and found to be much less active (1000-fold) highlighting the exceptional characteristics of 1... - Design, synthesis, and biological evaluation of simplified alpha-keto heterocycle, trifluoromethyl ketone, and formyl substituted folate analogues as potential inhibitors of GAR transformylase and AICAR transformylaseThomas H Marsilje
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Bioorg Med Chem 11:4487-501. 2003.... - Design, synthesis, and biological evaluation of 10-methanesulfonyl-DDACTHF, 10-methanesulfonyl-5-DACTHF, and 10-methylthio-DDACTHF as potent inhibitors of GAR Tfase and the de novo purine biosynthetic pathwayHeng Cheng
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Bioorg Med Chem 13:3577-85. 2005..0 microM and 2, IC50 = 2.0 microM)... - The oligomeric T4 primase is the functional form during replicationJingsong Yang
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
J Biol Chem 280:25416-23. 2005..Collectively, these results provide strong evidence for the functional oligomerization of gp61. The potential roles of gp61 oligomerization during lagging strand synthesis are discussed... - RNA primer handoff in bacteriophage T4 DNA replication: the role of single-stranded DNA-binding protein and polymerase accessory proteinsScott W Nelson
Department of Chemistry, Pennsylvania State University, University Park, Pennsylvania 16802, USA
J Biol Chem 283:22838-46. 2008..The interplay between gp32, primase, clamp, and clamp loader dictates the rate and efficiency of primer synthesis, polymerase recycling, and primer transfer to the polymerase... - Single-molecule studies of DNA replisome functionSenthil K Perumal
414 Wartik Laboratory, Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA
Biochim Biophys Acta 1804:1094-112. 2010.... - The dynamic processivity of the T4 DNA polymerase during replicationJingsong Yang
Department of Chemistry, 414 Wartik Laboratory, Pennsylvania State University, University Park, PA 16802, USA
Proc Natl Acad Sci U S A 101:8289-94. 2004.... - Assembly of the bacteriophage T4 helicase: architecture and stoichiometry of the gp41-gp59 complexFaoud T Ishmael
Department of Chemistry, Pennsylvania State University, University Park, Pennsylvania 16802, USA
J Biol Chem 277:20555-62. 2002..As the helicase is loaded onto DNA, a conformational change in the gp41-gp59 complex occurs, which may serve to displace gp32 from the lagging strand and load the hexameric helicase in its place... - Using incremental truncation to create libraries of hybrid enzymesAlexander R Horswill
Department of Chemistry, Pennsylvania State University, University Park 16802, USA
Methods Enzymol 388:50-60. 2004 - A universal, vector-based system for nucleic acid reading-frame selectionStefan Lutz
Department of Chemistry, The Pennsylvania State University, 414 Wartik Laboratory, University Park, PA 16802, USA
Protein Eng 15:1025-30. 2002.... - A nonradioactive DNA methyltransferase assay adaptable to high-throughput screeningYoun-Hi Woo
414 Wartik Laboratory, Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA
Anal Biochem 340:336-40. 2005..The methodology developed is suited to screen a large number of compounds for inhibitors of various methyltransferases... - The structure of a ring-opened proliferating cell nuclear antigen-replication factor C complex revealed by fluorescence energy transferZhihao Zhuang
Department of Chemistry, 414 Wartik Laboratory, Pennsylvania State University, University Park, PA 16802, USA
Proc Natl Acad Sci U S A 103:2546-51. 2006..The information derived from this work complements that obtained from previous structural and mechanistic studies and provides a more complete picture of a eukaryotic clamp-loading pathway using yeast as a paradigm... - Identification of a novel boron-containing antibacterial agent (AN0128) with anti-inflammatory activity, for the potential treatment of cutaneous diseasesStephen J Baker
Anacor Pharmaceuticals, Inc, 1060 E Meadow Circle, Palo Alto, CA 94303, USA
Bioorg Med Chem Lett 16:5963-7. 2006..This compound is now in clinical development for dermatological conditions... - Design and evolution of new catalytic activity with an existing protein scaffoldHee-Sung Park
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 373-1, Kusung-dong, Yusung-gu, Daejon 305-701, Korea
Science 311:535-8. 2006..8 x 10(2) (mole/liter)(-1) second(-1), thus increasing resistance to Escherichia coli growth on cefotaxime by a factor of about 100... - Role of a solvent-exposed tryptophan in the recognition and binding of antibiotic substrates for a metallo-beta-lactamaseJames J A Huntley
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Protein Sci 12:1368-75. 2003..Rather, a more productive approach may be to design therapeutics directed towards this solvent-exposed tryptophan residue... - Rational design, synthesis, evaluation, and crystal structure of a potent inhibitor of human GAR Tfase: 10-(trifluoroacetyl)-5,10-dideazaacyclic-5,6,7,8-tetrahydrofolic acidYan Zhang
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Biochemistry 42:6043-56. 2003.... - Structure of avian AICAR transformylase with a multisubstrate adduct inhibitor beta-DADF identifies the folate binding siteDennis W Wolan
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Biochemistry 42:10904-14. 2003..Furthermore, the beta-DADF-bound structure provides a more optimal three-dimensional scaffold to improve the design of specific antineoplastic agents... - PurT-encoded glycinamide ribonucleotide transformylase. Accommodation of adenosine nucleotide analogs within the active siteJames B Thoden
Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706, USA
J Biol Chem 277:23898-908. 2002..This sensitivity to nucleotide identity is in sharp contrast to that observed for the "P-loop"-containing enzymes, in which the conformation of the binding motif is virtually unchanged in the presence or absence of nucleotides... - Dihydrofolate reductase mutant with exceptional resistance to methotrexate but not to trimetrexatePamela Pineda
Departments of Medicinal Chemistry and of Genetics and Development, University of Minnesota, Minneapolis, Minnesota 55455, USA
J Med Chem 46:2816-8. 2003..5-fold higher for trimetrexate (TMTX). These findings suggest that F31A/F34A could be used for gene therapy to render normal cells resistant to MTX but sensitive to TMTX... - Using transcriptional-based systems for in vivo enzyme screeningSteven M Firestine
Department of Medicinal Chemistry, Mylan School of Pharmacy, Duquesne University, Pittsburgh, PA, USA
Methods Mol Biol 205:315-27. 2003 - Allosteric regulation and catalysis emerge via a common routeNina M Goodey
Montclair State University, Department of Chemistry and Biochemistry, 1 Normal Avenue, Montclair, New Jersey 07043, USA
Nat Chem Biol 4:474-82. 2008.... - 'Screw-cap' clamp loader proteins that threadZhihao Zhuang
Nat Struct Mol Biol 11:580-1. 2004 - Conformational changes in the active site loops of dihydrofolate reductase during the catalytic cycleRani P Venkitakrishnan
Department of Molecular Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA
Biochemistry 43:16046-55. 2004..The G121V mutation, at a position distant from the active site, interferes with coupled loop movements and appears to impair catalysis by destabilizing the closed Michaelis complex and introducing an extra step into the kinetic pathway... - DNA polymerase fidelity: kinetics, structure, and checkpointsCatherine M Joyce
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520 8114, USA
Biochemistry 43:14317-24. 2004.... - On the solution structure of the T4 sliding clamp (gp45)David Millar
Department of Molecular Biology MB-19, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Biochemistry 43:12723-7. 2004..The ramifications for replisome remodeling by this pathway are discussed... - Single-molecule investigation of the T4 bacteriophage DNA polymerase holoenzyme: multiple pathways of holoenzyme formationR Derike Smiley
Department of Biochemistry, Duke University Medical Center, Box 3711, Durham, North Carolina 27710, USA
Biochemistry 45:7990-7. 2006..In all cases, MgATP is required. The possible physiological significance of the various assembly pathways is discussed in the context of replication initiation and lagging strand synthesis during various stages of T4 phage replication... - Split-intein mediated circular ligation used in the synthesis of cyclic peptide libraries in E. coliAli Tavassoli
School of Chemistry, University of Southampton, Southampton SO17 1BJ, UK
Nat Protoc 2:1126-33. 2007..This protocol is expected to take around 3-4 weeks to implement... - Single-molecule and transient kinetics investigation of the interaction of dihydrofolate reductase with NADPH and dihydrofolateZhiquan Zhang
Department of Biochemistry, Duke University Medical Center, Box 3711, Durham, NC 27710, USA
Proc Natl Acad Sci U S A 101:2764-9. 2004..The results from stopped-flow and single-molecule methods are complementary and demonstrate that multiple conformations of both the enzyme and enzyme-substrate complexes exist... - Enhanced crossover SCRATCHY: construction and high-throughput screening of a combinatorial library containing multiple non-homologous crossoversYasuaki Kawarasaki
Department of Chemical Engineering, University of Texas, Austin, TX 78712, USA
Nucleic Acids Res 31:e126. 2003..Expression and high-throughput flow cytometric screening of the chimeric GST library identified several chimeric progeny that retained rat-like parental substrate specificity... - Evolution of highly active enzymes by homology-independent recombinationKarl E Griswold
Department of Chemistry and Biochemistry, University of Texas, Austin, TX 78712, USA
Proc Natl Acad Sci U S A 102:10082-7. 2005..These results highlight the power of combinatorial homology-independent and low-homology recombination methods for the generation of unique, highly active enzymes and also suggest a possible means of enzyme "humanization."..
Research Grants
- PHOSPHATE ACTIVATION MECHANISMSSTEPHEN BENKOVIC; Fiscal Year: 2009..In so far as these events are central to cell division in how helicases in particular function in normal and diseased states is of critical importance. ..
- TRANSFORMYLASE ENZYMES--DIHYDROFOLATE REDUCTASESTEPHEN BENKOVIC; Fiscal Year: 2000..These folate requiring enzymes are important in one carbon unit transfer and have been the target of chemotherapy. Dihydrofolate reductase in particular serves as a paradigm for understanding the fundamentals of enzyme catalysis. ..
- PHOSPHATE ACTIVATION MECHANISMSSTEPHEN BENKOVIC; Fiscal Year: 2002..These studies should greatly deepen our knowledge of how the T4 replicative system functions and serves as a paradigm for DNA replication in general. ..
- PHOSPHATE ACTIVATION MECHANISMSSTEPHEN BENKOVIC; Fiscal Year: 2003..abstract_text> ..
- TRANSFORMYLASE ENZYMES DIHYDROFOLATE REDUCTASEStephen J Benkovic; Fiscal Year: 2010..Individual enzymes within the pathway are biologically validated targets. Interference by small molecules with purinosome assembly provides a unique route to new pharmaceuticals. ..
- PHOSPHATE ACTIVATION MECHANISMSStephen J Benkovic; Fiscal Year: 2010....
- TRANSFORMYLASE ENZYMES DIHYDROFOLATE REDUCTASESTEPHEN BENKOVIC; Fiscal Year: 2009..Individual enzymes within the pathway are biologically validated targets. Interference by small molecules with purinosome assembly provides a unique route to new pharmaceuticals. ..
- PHOSPHATE ACTIVATION MECHANISMSSTEPHEN BENKOVIC; Fiscal Year: 2009....
- PHOSPHATE ACTIVATION MECHANISMSSTEPHEN BENKOVIC; Fiscal Year: 2007....
- PHOSPHATE ACTIVATION MECHANISMSSTEPHEN BENKOVIC; Fiscal Year: 2006..abstract_text> ..
- TRANSFORMYLASE ENZYMES DIHYDROFOLATE REDUCTASESTEPHEN BENKOVIC; Fiscal Year: 2004..Computer models will be developed based on the determination of enzyme and metabolite levels in the cell to predict the flux of intermediates in the pathway. ..
- THE TRANSFORMYLASE ENZYMESSTEPHEN BENKOVIC; Fiscal Year: 1980....
- PHOSPHATE ACTIVATION MECHANISMSSTEPHEN BENKOVIC; Fiscal Year: 1980..Petsko at M.I.T. to carry out X-ray crystallographic studies on FBPase; and 5) initiation of series of mechanistic studies on restriction endonucleases commencing with the chemical synthesis of small, potential substrate molecules. ..
- PHOSPHATE ACTIVATION MECHANISMSSTEPHEN BENKOVIC; Fiscal Year: 1993..The ultimate objective of this work is to elucidate the relationship between polymerase structure and function that results in the enzymes high catalytic efficiency and fidelity...