NDLI: Multiple diverse ligands binding at a single protein site: a matter of pre-existing populations.

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Multiple diverse ligands binding at a single protein site: a matter of pre-existing populations.

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Multiple diverse ligands binding at a single protein site: a matter of pre-existing populations.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Shatsky, Maxim Nussinov, Ruth Wolfson, Haim J. Ma, Buyong
Description	Country affiliation: United States Author Affiliation: Ma B ( Laboratory of Experimental and Computational Biology, National Cancer Institute-Frederick, Frederick, Maryland 21702, USA.)
Abstract	Here, we comment on the steadily increasing body of data showing that proteins with specificity actually bind ligands of diverse shapes, sizes, and composition. Such a phenomenon is not surprising when one considers that binding is a dynamic process with populations in equilibrium and that the shape of the binding site is strongly influenced by the molecular partner. It derives implicitly from the concept of populations. All proteins, specific and nonspecific, exist in ensembles of substates. If the library of ligands in solution is large enough, favorably matching ligands with altered shapes and sizes can be expected to bind, with a redistribution of the protein populations. Point mutations at spatially distant sites may exert large conformational rearrangements and hinge effects, consistent with mutations away from the binding site leading to population shifts and (cross-)drug resistance. A similar effect is observed in protein superfamilies, in which different sequences with similar topologies display similar large-scale dynamic motions. The hinges are frequently at analogous sites, yet with different substrate specificity. Similar topologies yield similar conformational isomers, although with different distributions of population times, owing to the change in the conditions, that is, the change in the sequences. In turn, different distributions relate to binding of different sizes and shapes. Hence, the binding site shape and size are defined by the ligand. They are not independent entities of fixed proportions and cannot be analyzed independently of the binding partner. Such a proposition derives from viewing proteins as dynamic distributions, presenting to the incoming ligands a range of binding site shapes. It illustrates how presumably specific binding molecules can bind multiple ligands. In terms of drug design, the ability of a single receptor to recognize many dissimilar ligands shows the need to consider more diverse molecules. It provides a rationale for higher affinity inhibitors that are not derived from substrates at their transition states and indicates flexible docking schemes.
ISSN	09618368
e-ISSN	1469896X
Journal	Protein Science
Issue Number	2
Volume Number	11
Language	English
Publisher	Wiley-Blackwell (on behalf of The Protein Society)
Publisher Date	2002-02-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Ligands Proteins Metabolism Binding Sites Combinatorial Chemistry Techniques Models, Molecular Models, Theoretical Protein Binding Protein Conformation Research Support, Non-u.s. Gov't Research Support, U.s. Gov't, P.h.s. Discipline Biochemistry
Content Type	Text
Resource Type	Article
Subject	Medicine Molecular Biology Biochemistry

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