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Cited by 424Protein Structure and DynamicsReceptor Mechanisms and SignalingProtein Interaction Studies and Fluorescence Analysis

The DOI matches its Crossref record; 80 of the 81 references it cites were found in a registry or an index.

Multiple diverse ligands binding at a single protein site: A matter of pre‐existing populations

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Ma, Buyong, Shatsky, Maxim, Wolfson, Haim J., Nussinov, Ruth·2002·Protein Science
DOI 10.1110/ps.21302PMC PMC2373439
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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.

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Research works printed but not linked: 4

  1. 10.1002/1097-0134(2000)41:4 <63::AID-PROT60>3.0.CO;2-6 · DOI
  2. Nussinov R., 2001, Current topics in computational biology
  3. ShatskyM.2001.“Alignment of flexible protein structures.”M.Sc. thesis Tel Aviv University.
  4. 10.1042/0300-5127:0280517 · DOI

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Metadata

Authors
Ma, B., Shatsky, M., Wolfson, H. J., & Nussinov, R.
Affiliations
  • National Cancer Institute (US)
  • Tel Aviv University (IL)
Corresponding author
Nussinov, Ruth
ORCID
Venue
Protein Science
Publisher
Wiley
Published
2002-02
Volume
11
Issue
2
Pages
184-197
ISSN
  • 0961-8368 (ISSN-L)
  • 1469-896X
DOI
10.1110/ps.21302
PMC
PMC2373439
OpenAlex
W2112053365
Cited by
420
References
81
Citations by year
2026: 5 · 2025: 15 · 2024: 7 · 2023: 16 · 2022: 12 · 2021: 15 · 2020: 13 · 2019: 20 · 2018: 20 · 2017: 10 · 2016: 13 · 2015: 16 · 2014: 17 · 2013: 28 · 2012: 20
FWCI
1.71
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 2526 d)
Locations
  • Protein Science (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (n01co12400-79-0-22)
  • National Cancer Institute (N01CO12400, N01-CO-012400)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
Keywords
ligand specificity, protein conformational ensembles, protein dynamics, ligand-induced conformational change, point mutations, protein superfamilies, conformational isomers, flexible docking, drug design
MeSH terms
Binding Sites, Ligands, Models, Molecular, Models, Theoretical, Protein Binding, Protein Conformation, Proteins, Combinatorial Chemistry Techniques

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