Multiple diverse ligands binding at a single protein site: A matter of pre‐existing populations
Open accessAbstract
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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Such binding-site conformational gradients can favorably interact with ensembles of ligands of different sizes.
“These can potentially favorably interact with ensembles of ligands of variable sizes.219,225”
From Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell (2016) · cites this paper as [219]
Hinge regions that adopt multiple conformations often act as binding sites for several ligands.
“Hinge sites with multiple conformations are often the binding sites for multiple-ligands,219”
From Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell (2016) · cites this paper as [219]
The distributions and variability of conformers provide a gradient of binding-site shapes and volumes.
“Depending on the distributions of the conformers and their conformational variability, they provide a gradient of binding site conformations of different shapes and volumes.”
From Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell (2016) · cites this paper as [219]
Protein dynamics are universally important for protein-ligand interaction.
“Protein dynamics have been shown to be universally important for protein-ligand interaction.219”
From Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell (2016) · cites this paper as [219]
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Binding-Induced Folding of a Natively Unstructured Transcription Factor
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Latent evolutionary potentials under the neutral mutational drift of an enzyme
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A human monoclonal antibody neutralizes diverse HIV-1 isolates by binding a critical gp41 epitope
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Principles of Allosteric Interactions in Cell Signaling
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Self-citationRelation between native ensembles and experimental structures of proteins
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Conformational Transitions upon Ligand Binding: Holo-Structure Prediction from Apo Conformations
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New concepts in pharmacological efficacy at 7 TM receptors: IUPHAR R eview 2
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Crystal structures of the two major aggrecan degrading enzymes, ADAMTS4 and ADAMTS5
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Multiple conformational selection and induced fit events take place in allosteric propagation
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- Authors
- Ma, B., Shatsky, M., Wolfson, H. J., & Nussinov, R.
- Affiliations
- National Cancer Institute (US)
- Tel Aviv University (IL)
- Corresponding author
- Nussinov, Ruth
- Venue
- Protein Science
- Publisher
- Wiley
- Published
- 2002-02
- Volume
- 11
- Issue
- 2
- Pages
- 184-197
- ISSN
- 0961-8368 (ISSN-L)
- 1469-896X
- 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
- bronze
- doi.org
- 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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