Genomes and Genes
Experts and Doctors on structure activity relationship in Cambridge, Massachusetts, United States
Locale: Cambridge, Massachusetts, United States
Topic: structure activity relationship
- Yang J, Laymon R, Goldstein L. A three-domain structure of kinesin heavy chain revealed by DNA sequence and microtubule binding analyses. Cell. 1989;56:879-89 pubmed..These data suggest that kinesin has an organization very similar to that of myosin even though there are no obvious sequence similarities between the two molecules. ..
- Bridger G, Skerlj R, Hernandez Abad P, Bogucki D, Wang Z, Zhou Y, et al. Synthesis and structure-activity relationships of azamacrocyclic C-X-C chemokine receptor 4 antagonists: analogues containing a single azamacrocyclic ring are potent inhibitors of T-cell tropic (X4) HIV-1 replication. J Med Chem. 2010;53:1250-60 pubmed publisher..0 nM). More importantly, however, the key structural elements of 1 required for antiviral activity may facilitate the design of nonmacrocyclic CXCR4 antagonists suitable for HIV treatment via oral administration. ..
- Napper A, Hixon J, McDonagh T, Keavey K, Pons J, Barker J, et al. Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1. J Med Chem. 2005;48:8045-54 pubmed..These SIRT1 inhibitors are low molecular weight, cell-permeable, orally bioavailable, and metabolically stable. These compounds provide chemical tools to study the biology of SIRT1 and to explore therapeutic uses for SIRT1 inhibitors. ..
- Vu C, Peng B, Kumaravel G, Smits G, Jin X, Phadke D, et al. Piperazine derivatives of [1,2,4]triazolo[1,5-a][1,3,5]triazine as potent and selective adenosine A2a receptor antagonists. J Med Chem. 2004;47:4291-9 pubmed..For instance, compound 34 was orally active in the rat catalepsy model at 3 mg/kg. In the 6-hydroxydopamine-lesioned rat model, this compound was also quite effective, with a minimum effective dose of 3 mg/kg po. ..
- Wang Y, Strickland C, Voigt J, Kennedy M, Beyer B, Senior M, et al. Application of fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design to identify novel microM leads for the development of nM BACE-1 (beta-site APP cleaving enzyme 1) inhibitors. J Med Chem. 2010;53:942-50 pubmed publisher..The structure-based design of a cyclic acylguanidine lead series and its optimization into nanomolar BACE-1 inhibitors are the subject of the companion paper ..
- Cheng C, Shipps G, Yang Z, Kawahata N, Lesburg C, Duca J, et al. Inhibitors of hepatitis C virus polymerase: synthesis and characterization of novel 2-oxy-6-fluoro-N-((S)-1-hydroxy-3-phenylpropan-2-yl)-benzamides. Bioorg Med Chem Lett. 2010;20:2119-24 pubmed publisher..These data warrant further lead optimization efforts on this novel series of non-nucleoside inhibitors targeting the HCV polymerase. ..
- Banerjee A, Yang W, Karplus M, Verdine G. Structure of a repair enzyme interrogating undamaged DNA elucidates recognition of damaged DNA. Nature. 2005;434:612-8 pubmed..The structure reveals a remarkably effective gate-keeping strategy for lesion discrimination and suggests a mechanism for oxoG insertion into the hOGG1 active site. ..
- Meredith E, Beattie K, Burgis R, Capparelli M, Chapo J, DiPietro L, et al. Identification of potent and selective amidobipyridyl inhibitors of protein kinase D. J Med Chem. 2010;53:5422-38 pubmed publisher..The in vivo efficacy of a representative example compound on heart morphology is reported herein. ..
- Charifson P, Grillot A, Grossman T, Parsons J, Badia M, Bellon S, et al. Novel dual-targeting benzimidazole urea inhibitors of DNA gyrase and topoisomerase IV possessing potent antibacterial activity: intelligent design and evolution through the judicious use of structure-guided design and structure-activity relationships. J Med Chem. 2008;51:5243-63 pubmed publisher..Data are presented for enzyme inhibition, antibacterial activity, and in vivo efficacy by oral and intravenous administration in two rodent infection models. ..
- de Arruda M, Watson S, Lin C, Leavitt J, Matsudaira P. Fimbrin is a homologue of the cytoplasmic phosphoprotein plastin and has domains homologous with calmodulin and actin gelation proteins. J Cell Biol. 1990;111:1069-79 pubmed..Neoplastic cells derived from solid tissues express both isoforms. The differences in expression, sequence, and phosphorylation suggest possible functional differences between fimbrin isoforms. ..
- Huang W, Zhu X, Wang Y, Azam M, Wen D, Sundaramoorthi R, et al. 9-(Arenethenyl)purines as dual Src/Abl kinase inhibitors targeting the inactive conformation: design, synthesis, and biological evaluation. J Med Chem. 2009;52:4743-56 pubmed publisher..Notably, several inhibitors (e.g., 14a, AP24163) exhibited modest cellular potency (IC50 = 300-400 nM) against the Bcr-Abl mutant T315I, a variant resistant to all currently marketed therapies for chronic myeloid leukemia. ..
- Bruner S, Norman D, Verdine G. Structural basis for recognition and repair of the endogenous mutagen 8-oxoguanine in DNA. Nature. 2000;403:859-66 pubmed..One known mutation, R154H, converts hOGG1 to a promutator by relaxing the specificity of the enzyme for the base opposite oxoG. ..
- Chuaqui C, Deng Z, Singh J. Interaction profiles of protein kinase-inhibitor complexes and their application to virtual screening. J Med Chem. 2005;48:121-33 pubmed..Interaction-based analysis should provide a valuable tool for understanding inhibitor binding to other important drug targets. ..
- Martin M, Newcomb J, Nunes J, McGowan D, Armistead D, Boucher C, et al. Novel 2-aminopyrimidine carbamates as potent and orally active inhibitors of Lck: synthesis, SAR, and in vivo antiinflammatory activity. J Med Chem. 2006;49:4981-91 pubmed
- Ding T, Lee S, Rochet J, Lansbury P. Annular alpha-synuclein protofibrils are produced when spherical protofibrils are incubated in solution or bound to brain-derived membranes. Biochemistry. 2002;41:10209-17 pubmed..Thus, abnormal membrane permeabilization may be a pathogenic mechanism in PD. ..
- Jin L, Wei W, Jiang Y, Peng H, Cai J, Mao C, et al. Crystal structures of human SIRT3 displaying substrate-induced conformational changes. J Biol Chem. 2009;284:24394-405 pubmed publisher..These structures and biophysical studies provide key insight into the structural and functional relationship of the SIRT3 deacetylation activity. ..
- Wang J, Yan Y, Garrett T, Liu J, Rodgers D, Garlick R, et al. Atomic structure of a fragment of human CD4 containing two immunoglobulin-like domains. Nature. 1990;348:411-8 pubmed..The binding sites for monoclonal antibodies, class II major histocompatibility complex molecules, and human immunodeficiency virus gp120 can be mapped on the molecular surface. ..
- ter Haar E, Coll J, Austen D, Hsiao H, Swenson L, Jain J. Structure of GSK3beta reveals a primed phosphorylation mechanism. Nat Struct Biol. 2001;8:593-6 pubmed..The structure explains the unique primed phosphorylation mechanism of GSK3beta and how GSK3beta relies on a phosphoserine in the substrate for the alignment of the beta- and alpha-helical domains. ..
- Barberis A, Pearlberg J, Simkovich N, Farrell S, Reinagel P, Bamdad C, et al. Contact with a component of the polymerase II holoenzyme suffices for gene activation. Cell. 1995;81:359-68 pubmed..From these observations and further analyses of GAL11, we propose that a single activator-holoenzyme contact can trigger gene activation simply by recruiting the latter to DNA. ..
- Cheng C, Shipps G, Yang Z, Sun B, Kawahata N, Soucy K, et al. Discovery and optimization of antibacterial AccC inhibitors. Bioorg Med Chem Lett. 2009;19:6507-14 pubmed publisher..This compound is a potent and selective inhibitor of bacterial AccC with an IC(50) of 20 nM and a MIC of 0.8 microg/mL against a sensitized strain of Escherichia coli (HS294 E. coli). ..
- von Grotthuss M, Plewczynski D, Ginalski K, Rychlewski L, Shakhnovich E. PDB-UF: database of predicted enzymatic functions for unannotated protein structures from structural genomics. BMC Bioinformatics. 2006;7:53 pubmed..http://paradox.harvard.edu/PDB-UF and http://bioinfo.pl/PDB-UF. ..
- Phelps C, Wang R, Choo S, Gaudet R. Differential regulation of TRPV1, TRPV3, and TRPV4 sensitivity through a conserved binding site on the ankyrin repeat domain. J Biol Chem. 2010;285:731-40 pubmed publisher..Different feedback mechanisms likely arose because of the different physiological stimuli or temperature thresholds of these channels. ..
- Dynlacht B, Moberg K, Lees J, Harlow E, Zhu L. Specific regulation of E2F family members by cyclin-dependent kinases. Mol Cell Biol. 1997;17:3867-75 pubmed..Thus, both enzymatic phosphorylation and stable physical interaction are necessary for the specific regulation of E2F family members by cyclin-dependent kinases. ..
- Yarm F. Plk phosphorylation regulates the microtubule-stabilizing protein TCTP. Mol Cell Biol. 2002;22:6209-21 pubmed..These results suggest that phosphorylation decreases the microtubule-stabilizing activity of TCTP and promotes the increase in microtubule dynamics that occurs after metaphase. ..
- Vos T, Caracoti A, Che J, Dai M, Farrer C, Forsyth N, et al. Identification of 2-[2-[2-(5-bromo-2- methoxyphenyl)-ethyl]-3-fluorophenyl]-4,5-dihydro-1H-imidazole (ML00253764), a small molecule melanocortin 4 receptor antagonist that effectively reduces tumor-induced weight loss in a mouse model. J Med Chem. 2004;47:1602-4 pubmed..We report here the identification of a novel nonpeptidic MC4R antagonist and its effects on tumor-induced weight loss in mice following peripheral administration...
- Marykwas D, Berg H. A mutational analysis of the interaction between FliG and FliM, two components of the flagellar motor of Escherichia coli. J Bacteriol. 1996;178:1289-94 pubmed..This clustering, when compared with results of previous studies, suggests that the FliG-FliM interaction plays a central role in switching. ..
- Silver S, Davies E, Doyon L, Rebay I. Functional dissection of eyes absent reveals new modes of regulation within the retinal determination gene network. Mol Cell Biol. 2003;23:5989-99 pubmed..Our data suggest that EYA requires homo- and heterotypic interactions and RAS/MAPK signaling responsiveness to ensure context-appropriate RD gene network activity. ..
- Kaila N, Janz K, DeBernardo S, Bedard P, Camphausen R, Tam S, et al. Synthesis and biological evaluation of quinoline salicylic acids as P-selectin antagonists. J Med Chem. 2007;50:21-39 pubmed..Lead compound 36 was efficacious in the rat AIA model of rheumatoid arthritis. ..
- Jacobs M, Hayakawa K, Swenson L, Bellon S, Fleming M, Taslimi P, et al. The structure of dimeric ROCK I reveals the mechanism for ligand selectivity. J Biol Chem. 2006;281:260-8 pubmed..Hydroxyfasudil, a metabolite of fasudil, may be selective for ROCK over PKA through a reversed binding orientation. ..
- Gross C, Parsons J, Grossman T, Charifson P, Bellon S, Jernee J, et al. Active-site residues of Escherichia coli DNA gyrase required in coupling ATP hydrolysis to DNA supercoiling and amino acid substitutions leading to novobiocin resistance. Antimicrob Agents Chemother. 2003;47:1037-46 pubmed..Four new residues (D73, G77, I78, and T165) that, when changed to the appropriate amino acid, result in both significant levels of novobiocin resistance and maintain in vivo function were identified in E. coli. ..
- Lee K, Foley M, Chen L, Behnke M, Lovering F, Kirincich S, et al. Discovery of Ecopladib, an indole inhibitor of cytosolic phospholipase A2alpha. J Med Chem. 2007;50:1380-400 pubmed..Compound 123 (Ecopladib) is a sub-micromolar inhibitor of cPLA2alpha in the GLU micelle and rat whole blood assays. Compound 123 displayed oral efficacy in the rat carrageenan air pouch and rat carrageenan-induced paw edema models. ..
- Murre C, McCaw P, Baltimore D. A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell. 1989;56:777-83 pubmed..Remarkable is the stringent conservation of hydrophobic residues present in both helices. We demonstrate that this new motif plays a crucial role in both dimerization and DNA binding. ..
- Miller Moslin K, Peukert S, Jain R, McEwan M, Karki R, Llamas L, et al. 1-amino-4-benzylphthalazines as orally bioavailable smoothened antagonists with antitumor activity. J Med Chem. 2009;52:3954-68 pubmed publisher..This compound displayed a good pharmacokinetic profile and also afforded tumor regression in a genetic mouse model of medulloblastoma. ..
- Somers W, Tang J, Shaw G, Camphausen R. Insights into the molecular basis of leukocyte tethering and rolling revealed by structures of P- and E-selectin bound to SLe(X) and PSGL-1. Cell. 2000;103:467-79 pubmed..These structures reveal differences in how E- and P-selectin bind SLe(X) and the molecular basis of the high-affinity interaction between P-selectin and PSGL-1. ..
- Pizzirani D, Roberti M, Grimaudo S, Di Cristina A, Pipitone R, Tolomeo M, et al. Identification of biphenyl-based hybrid molecules able to decrease the intracellular level of Bcl-2 protein in Bcl-2 overexpressing leukemia cells. J Med Chem. 2009;52:6936-40 pubmed publisher..Compounds 1, 3, 4, and 6 showed well-defined activity on apoptosis and differentiation, making them potential leads for development as new anticancer agents and chemical probes to study signaling networks in neoplastic cells. ..
- Sugawara M, Scholl T, Ponath P, Strominger J. A factor that regulates the class II major histocompatibility complex gene DPA is a member of a subfamily of zinc finger proteins that includes a Drosophila developmental control protein. Mol Cell Biol. 1994;14:8438-50 pubmed..Antisense cDNA to clone 18 inhibited the expression of a reporter construct containing the DPA promoter, indicating its functional importance in the expression of this class II gene. ..
- Loeb J, Davis L, Fink G. NUP2, a novel yeast nucleoporin, has functional overlap with other proteins of the nuclear pore complex. Mol Biol Cell. 1993;4:209-22 pubmed..This genetic evidence of overlapping function suggests that the nucleoporins act in concert, perhaps participating in the same step of the recognition or transit of macromolecules through the NPC. ..
- Lan T, Dai M, Wang D, Zhu F, Kandimalla E, Agrawal S. Toll-like receptor 7 selective synthetic oligoribonucleotide agonists: synthesis and structure-activity relationship studies. J Med Chem. 2009;52:6871-9 pubmed publisher..In conclusion, we have designed and synthesized novel SIMRA compounds that selectively act as agonists of TLR7. ..
- Sintchak M, Fleming M, Futer O, Raybuck S, Chambers S, Caron P, et al. Structure and mechanism of inosine monophosphate dehydrogenase in complex with the immunosuppressant mycophenolic acid. Cell. 1996;85:921-30 pubmed
- Fox T, Coll J, Xie X, Ford P, Germann U, Porter M, et al. A single amino acid substitution makes ERK2 susceptible to pyridinyl imidazole inhibitors of p38 MAP kinase. Protein Sci. 1998;7:2249-55 pubmed..T110A. These ATP binding site substitutions induce low nanomolar sensitivity to pyridinyl imidazoles. Furthermore, we identified 5-iodotubercidin as a potent ERK2 inhibitor, which may help reveal the role of ERK2 in cell proliferation. ..
- Fuse S, Tsukamoto H, Yuan Y, Wang T, Zhang Y, Bolla M, et al. Functional and structural analysis of a key region of the cell wall inhibitor moenomycin. ACS Chem Biol. 2010;5:701-11 pubmed publisher..The reported work provides information and validated computational methods critical for the design of analogues based on moenomycin scaffolds. ..
- Sako D, Comess K, Barone K, Camphausen R, Cumming D, Shaw G. A sulfated peptide segment at the amino terminus of PSGL-1 is critical for P-selectin binding. Cell. 1995;83:323-31 pubmed..We propose that this sulfotyrosine-containing segment of PSGL-1, in conjunction with sLex presented on O-linked glycans, constitutes the high affinity P-selectin-binding site. ..
- Nonet M, Young R. Intragenic and extragenic suppressors of mutations in the heptapeptide repeat domain of Saccharomyces cerevisiae RNA polymerase II. Genetics. 1989;123:715-24 pubmed..We propose that the SRB2 gene encodes a factor that is involved in RNA synthesis and may interact with the CTR domain of the large subunit of RNA polymerase II. ..
- Bellon S, Parsons J, Wei Y, Hayakawa K, Swenson L, Charifson P, et al. Crystal structures of Escherichia coli topoisomerase IV ParE subunit (24 and 43 kilodaltons): a single residue dictates differences in novobiocin potency against topoisomerase IV and DNA gyrase. Antimicrob Agents Chemother. 2004;48:1856-64 pubmed..These data demonstrate that the ParE M74 and GyrB I78 side chains impart opposite effects on the enzyme's substrate affinity and catalytic efficiency. ..
- Lovering F, Bikker J, Humblet C. Escape from flatland: increasing saturation as an approach to improving clinical success. J Med Chem. 2009;52:6752-6 pubmed publisher..In an attempt to explain these observations, we further demonstrate that saturation correlates with solubility, an experimental physical property important to success in the drug discovery setting. ..
- Cho Y, Borland M, Brain C, Chen C, Cheng H, Chopra R, et al. 4-(Pyrazol-4-yl)-pyrimidines as selective inhibitors of cyclin-dependent kinase 4/6. J Med Chem. 2010;53:7938-57 pubmed publisher..Significant selectivity for CDK4/6 over CDK1 and CDK2 was demonstrated with several compounds in both enzymatic and cellular assays. ..
- Chicz R, Urban R, Lane W, Gorga J, Stern L, Vignali D, et al. Predominant naturally processed peptides bound to HLA-DR1 are derived from MHC-related molecules and are heterogeneous in size. Nature. 1992;358:764-8 pubmed
- Pittman D, Wang J, Kaufman R. Identification and functional importance of tyrosine sulfate residues within recombinant factor VIII. Biochemistry. 1992;31:3315-25 pubmed..These results suggest that tyrosine sulfation is required for full factor VIII activity and may affect the interaction of factor VIII with other components of the coagulation cascade. ..
- Myers L, Terranova M, Nash H, Markus M, Verdine G. Zinc binding by the methylation signaling domain of the Escherichia coli Ada protein. Biochemistry. 1992;31:4541-7 pubmed
- Raman R, Myette J, Shriver Z, Pojasek K, Venkataraman G, Sasisekharan R. The heparin/heparan sulfate 2-O-sulfatase from Flavobacterium heparinum. A structural and biochemical study of the enzyme active site and saccharide substrate specificity. J Biol Chem. 2003;278:12167-74 pubmed..This combinatorial approach of structure modeling and biochemical studies provides insight into the molecular basis of enzyme function. ..
- Sintchak M, Arjara G, Kellogg B, Stubbe J, Drennan C. The crystal structure of class II ribonucleotide reductase reveals how an allosterically regulated monomer mimics a dimer. Nat Struct Biol. 2002;9:293-300 pubmed publisher..Thus, L. leichmannii RNR is a paradigm for the simplest structural entity capable of ribonucleotide reduction, a reaction linking the RNA and DNA worlds...
- Blobe G, Schiemann W, Pepin M, Beauchemin M, Moustakas A, Lodish H, et al. Functional roles for the cytoplasmic domain of the type III transforming growth factor beta receptor in regulating transforming growth factor beta signaling. J Biol Chem. 2001;276:24627-37 pubmed..These studies, for the first time, elucidate important functional roles of the cytoplasmic domain of the type III receptor and demonstrate that these roles are essential for regulating TGF-beta signaling. ..
- Grozinger C, Chao E, Blackwell H, Moazed D, Schreiber S. Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening. J Biol Chem. 2001;276:38837-43 pubmed..Preliminary studies using one of these compounds suggest that inhibition of sirtuins interferes with body axis formation in Arabidopsis. ..
- Nicholas R, Strominger J. Site-directed mutants of a soluble form of penicillin-binding protein 5 from Escherichia coli and their catalytic properties. J Biol Chem. 1988;263:2034-40 pubmed..8 mM for PBP 5, PBP 5C-S, and PBP 5C-A, respectively, while the values for Vmax were 2.5, 3.3, and 5.1 mumol/min/mg. From these data it was concluded that the cysteine residue does not directly participate in the enzymatic mechanism. ..
- Houman F, Holm C. DBF8, an essential gene required for efficient chromosome segregation in Saccharomyces cerevisiae. Mol Cell Biol. 1994;14:6350-60 pubmed..Taken together, our data suggest that Dbf8p plays an essential role in chromosome segregation...
- Chou J, Li H, Salvesen G, Yuan J, Wagner G. Solution structure of BID, an intracellular amplifier of apoptotic signaling. Cell. 1999;96:615-24 pubmed..Additionally, we show that the overall structure of BID is preserved after cleavage by Caspase 8. We propose that BID has both BH3 domain-dependent and -independent modes of action in inducing mitochondrial damage. ..
- Foley J, Song X, Demidova T, Jalil F, Jilal F, Hamblin M. Synthesis and properties of benzo[a]phenoxazinium chalcogen analogues as novel broad-spectrum antimicrobial photosensitizers. J Med Chem. 2006;49:5291-9 pubmed..These data, taken with the findings of uptake and retention studies, suggest that the superior activity of selenium derivative 3 can be attributed to its much higher triplet quantum yield...
- Zhao X, Ghaffari S, Lodish H, Malashkevich V, Kim P. Structure of the Bcr-Abl oncoprotein oligomerization domain. Nat Struct Biol. 2002;9:117-20 pubmed..Two dimers then stack onto each other to form a tetramer. The Bcr1-72 structure provides a basis for the design of inhibitors of Bcr-Abl transforming activity by disrupting Bcr-Abl oligomerization. ..
- Sung K, Holm R. Functional analogue reaction systems of the DMSO reductase isoenzyme family: probable mechanism of S-oxide reduction in oxo transfer reactions mediated by bis(dithiolene)-tungsten(IV,VI) complexes. J Am Chem Soc. 2002;124:4312-20 pubmed..This work is the most detailed mechanistic investigation of oxo transfer mediated by a biological metal...
- Liu X, Wu H, Byrne M, Jeffrey J, Krane S, Jaenisch R. A targeted mutation at the known collagenase cleavage site in mouse type I collagen impairs tissue remodeling. J Cell Biol. 1995;130:227-37 pubmed..Thus, type I collagen is degraded by at least two differentially controlled mechanisms involving collagenases with distinct, but overlapping, substrate specificities. ..
- Krishnan R, Lindquist S. Structural insights into a yeast prion illuminate nucleation and strain diversity. Nature. 2005;435:765-72 pubmed..These findings resolve several problems in yeast prion biology and have broad implications for other amyloids. ..
- Fromme J, Banerjee A, Huang S, Verdine G. Structural basis for removal of adenine mispaired with 8-oxoguanine by MutY adenine DNA glycosylase. Nature. 2004;427:652-6 pubmed..These structures reveal the basis for recognizing both lesions in the A*oxoG pair and for catalysing removal of the adenine base. ..
- Murre C, McCaw P, Vaessin H, Caudy M, Jan L, Jan Y, et al. Interactions between heterologous helix-loop-helix proteins generate complexes that bind specifically to a common DNA sequence. Cell. 1989;58:537-44 pubmed..A role of E12 and E47 in mammalian development, analogous to that of daughterless in Drosophila, is likely. ..
- Blacklow S, Knowles J. How can a catalytic lesion be offset? The energetics of two pseudorevertant triosephosphate isomerases. Biochemistry. 1990;29:4099-108 pubmed..The results thus provide the beginnings of a detailed understanding of the kinetic refinement of enzyme catalysts...
- Widdison W, Wilhelm S, Cavanagh E, Whiteman K, Leece B, Kovtun Y, et al. Semisynthetic maytansine analogues for the targeted treatment of cancer. J Med Chem. 2006;49:4392-408 pubmed..The targeted delivery of these maytansinoids, using monoclonal antibodies, resulted in a high, specific killing of the targeted cells in vitro and remarkable antitumor activity in vivo. ..