Joel L Sussman

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..Sliding windows permit identification of large regions within a protein that possess folding propensities different from those of the whole protein...

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..Our proposed model explains the strong antagonistic activity of alpha-BTX and accommodates much of the biochemical data on the mode of interaction of alpha-BTX with the AChR...

..The structure permits a detailed description of PON1's active site and suggests possible mechanisms for its catalytic activity on certain substrates...

..Thus, the protein can assume these conformations even in the absence of the ligand that permitted their experimental detection. These observations are pertinent to structure-based drug design...

..The results also permitted the refinement of a mathematical model for estimating the efficacious dose of rePON1s variants required for prophylaxis in humans...

..This permits optimization of conditions at all stages of protein production and structure determination. A set of bioinformatics tools, which are implemented in our LIMS, is utilized to analyze each target...

..A proposal for the functional significance of the halotolerance of CA XIV in the kidney is presented...

..Together, these results have significance for understanding the mechanism of action of GlcCerase and the mode of GlcCerase chaperoning by imino sugars...

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..These differences in glycosylation affect cellular internalization; the rate of velaglucerase alfa internalization into human macrophages is at least 2-fold greater than that of imiglucerase...

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..It is proposed that flexibility of this loop may permit the binding of inhibitors such as galanthamine, which are too bulky to penetrate the narrow neck of the gorge formed by Tyr121 and Phe330 as seen in the crystal structure...

..The P59Q mutation in ColQ, which causes congenital endplate AChE deficiency, and is located within the PRAD, disrupts crucial WAT-WAT and WAT-PRAD interactions. A model is proposed for the synaptic AChE(T) tetramer...

..The noncovalent inhibitors vary greatly in their structures and bind to different sites of the enzyme, offering many different starting points for future drug design...

..Conformational changes upon ligand binding thus involve preexisting equilibrium dynamics. Consequently, rational drug design could benefit significantly from conformations monitored by MD simulations of native targets...

..However, several of these techniques indicate that it is not fully extended, but becomes significantly more extended under denaturing conditions...

..These findings may facilitate rational design of new meptazinol-based acetylcholinesterase inhibitors...

..Furthermore, both purified fractions of amalgam were shown to interact with Torpedo californica acetylcholinesterase, a structural homolog of neurotactin...

..PON3 also exhibits potentially anti-atherogenic functions, although at levels lower than those of PON1...

..Such analysis provides a new framework for determination of the structure of other Gaucher disease mutants and suggests new approaches for rational drug design...

..Our results further suggest that cyclodextrin derivatives might serve as suitable delivery systems of amphiphilic glycosidase inhibitors in a biomedical context...

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..Comparison of the structure of acid-beta-glucosidase with that of xylanase, a bacterial enzyme from a closely related protein family, demonstrates a close correspondence between the active-site residues of the two enzymes...

..We also discuss the stability of Cerezyme, which can be altered by modification of its N-glycan chains with possible implications for improved ERT in Gaucher disease...

..This rotation may allow some relaxation of the strict coplanarity of the aromatic rings in the bound thioflavin T and result in partial quenching of its fluorescence...

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..Modeling of the complexes of CPT-11 with mammalian butyrylcholinesterase and carboxylesterase, both of which are known to hydrolyze the drug, shows how binding to either of the two enzymes yields a productive substrate-enzyme complex...

..6 Å resolution. This structure provides important information pertinent to the design of novel functional ERα targeted probes for clinical applications...

..Its unique features make dCA I a useful model to understand the physico-chemical basis of halotolerance and protein-salt interactions in general...

..We also describe Proteopedia's use for 3D visualization in structure-related pedagogy...

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..This chapter describes a protocol for such automated systems, which permits easy construction of pH optimization grids using any desired fixed buffer set with varying ionic strengths directly dispensed into the crystallization plate...

..Both of these actions involve the so-called 'peripheral' anionic site at the entrance to the active-site gorge. Novel anticholinesterases are targeted against this site, rather than against the active site at the bottom of the gorge...

..Taken together, our results thus suggest that the 20S proteasome degradation assay provides a powerful system for operational definition of IUPs...

..The structure provides the possibility of engineering improved GlcCerase for enzyme-replacement therapy, and for designing structure-based drugs aimed at restoring the activity of defective GlcCerase...

..We then demonstrated the in vivo prophylactic activity of an evolved variant. These evolved variants and the newly developed screens provide the basis for engineering PON1 for prophylaxis against other G-type agents...

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..The procedure described in this article may serve as a paradigm for obtaining high-affinity peptides in biochemical systems that contain a ligand and a receptor molecule...

..The results offer new insights into factors affecting protein-ligand complementarity within the gorge and should assist the further development of improved AChE inhibitors...

..In addition, Gli-cyt was shown to possess charge and hydrophobic properties characteristic of natively unfolded proteins (i.e., proteins that, when purified, are intrinsically disordered under physiologic conditions in vitro)...

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..This tool is a plug-in for the open-source molecular graphics program PyMOL, and enables experts and novices alike to produce informative and high-quality molecular animations...

..This should lead to much improved management and tracking of structural genomics experimental data...

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..Finally, we report that species composition signatures preserve evolutionary memory, providing a new method to compare phylogenetic relationships among species that avoids problems of sequence alignment and ortholog detection...

..The asymmetric unit contains two molecules of the protein, which corresponds to V(M) = 2.65 A(3) Da(-1) and a solvent content of 52.7%...

..The relative strength of binding of bisquaternary inhibitors to acetylcholinesterase and the effect of several mutations of the enzyme are discussed in the context of the respective X-ray structures of their complexes with the enzyme...