Predicting protein interaction sites: binding hot-spots in protein–protein and protein–ligand interfaces

Burgoyne, Nicholas J.; Jackson, Richard M.

doi:10.1093/bioinformatics/btl079

Cited by 151 publications

(123 citation statements)

References 54 publications

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“…2). Surprisingly, KNO 3 and KCl dissociated the complex but KF did not, at least not to the same degree, and K 2 HPO 4 even increased the signal slightly. We then performed pre-equilibrium binding experiments with three different anions: chloride, fluoride, and phosphate.…”

Section: Resultsmentioning

confidence: 88%

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Two Conserved Residues Govern the Salt and pH Dependencies of the Binding Reaction of a PDZ Domain

Celestine

Engström

Gianni

et al. 2006

Journal of Biological Chemistry

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PDZ domains are protein-protein interaction modules found in hundreds of human proteins. Their binding reactions are sensitive to variations in salt and pH but the basis of the respective dependence has not been clear. We investigated the binding reaction between PSD-95 PDZ3 and a peptide corresponding to a native ligand with protein engineering in conjunction with stopped-flow and equilibrium fluorimetry and found that the two conserved residues Arg-318 and His-372 were responsible for the salt and pH dependencies, respectively. The basis of the salt-dependent variation of the affinity was explored by mutating all charged residues in and around the peptide-binding pocket. Arg-318 was found to be crucial, as mutation to alanine obliterated the effect of chloride on the binding constants. The direct interaction of chloride with Arg-318 was demonstrated by time-resolved urea denaturation experiments, where the Arg-318 3 Ala mutant was less stabilized by addition of chloride as compared with wild-type PDZ3. We also demonstrated that protonation of His-372 was responsible for the increase of the equilibrium dissociation constant at low pH. Both chloride concentration and pH (during ischemia) vary in the postsynaptic density, where PSD-95 is present, and the physiological buffer conditions may thus modulate the interaction between PSD-95 and its ligands through binding of chloride and protons to the "molecular switches" Arg-318 and His-372, respectively.In the post-genomic era there will be ever-increasing focus on protein-protein interactions (1-3) because of their critical role in cellular function and the growing sequence and structure databases. Indeed, most processes in the cell are governed by more or less specific protein-protein interactions. Often the binding is tuned by cellular or extracellular conditions such as pH, ionic strength, and molecular crowding, and also by specific molecules acting allosterically on the protein or competing with the "natural" ligand. Many proteins or protein domains, have evolved to interact with other proteins and form complexes, and one of the most common of these protein-protein interaction modules is the PDZ domain, which is present in several hundred human proteins (4, 5). PDZ domains are often found within multi-domain scaffolding proteins, and they bind mainly to the C termini of their target proteins (6 -8) but also internally (9, 10). PDZ domains have been shown to be rather promiscuous with regard to their ligand, and they have overlapping ligand specificities (6, 7).One of the most well studied PDZ domains is PDZ3 from PSD-95.3 The three-dimensional structure of this protein with and without its target ligand has been solved (11). The canonical PDZ domain consists of about 90 -100 amino acids forming six ␤ strands (␤A to ␤F) and two ␣ helices; ␣A and ␣B neatly arranged in a spherical structure (Fig. 1a). Peptide binding takes place between the ␤B strand and ␣B helix in an antiparallel manner as shown in Fig. 1a. As judged by the crystal structure, PDZ3 binds its targ...

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Section: Resultsmentioning

confidence: 88%

“…3 The three-dimensional structure of this protein with and without its target ligand has been solved (11). The canonical PDZ domain consists of about 90 -100 amino acids forming six ␤ strands (␤A to ␤F) and two ␣ helices; ␣A and ␣B neatly arranged in a spherical structure (Fig.…”

mentioning

confidence: 99%

Two Conserved Residues Govern the Salt and pH Dependencies of the Binding Reaction of a PDZ Domain

Celestine

Engström

Gianni

et al. 2006

Journal of Biological Chemistry

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“…It is well known that cation-interactions on the surface of proteins have a stabilizing effect on structure; however, we conclude based on our NMR data that mutations in Trp 30 and Lys 32 do not experience any significant structural destabilization. It is also well established that desolvation penalties can destabilize electrostatic interactions at protein-protein interaction interfaces (43,44) and that the desolvation penalty of a cation-interaction is significantly less than that of a normal electrostatic interaction (45). Given the importance of Lys 32 as an anchoring interaction for huwentoxin-IV binding and activity, it is tempting to speculate that the role of the cation-interaction is to mitigate the energetic cost that would otherwise be associated with desolvation of Lys 32 and thus strengthen the overall equilibrium constant more in favor of binding (anchored by Lys 32 -Glu 811 according to our model).…”

Section: Discussionmentioning

confidence: 99%

Analysis of the Structural and Molecular Basis of Voltage-sensitive Sodium Channel Inhibition by the Spider Toxin Huwentoxin-IV (μ-TRTX-Hh2a)

Minassian¹,

Gibbs²,

Shih

et al. 2013

Journal of Biological Chemistry

159

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Background:The molecular basis for sodium channel inhibition by spider venom peptides is poorly understood. Results: Key toxin residues and structural features important for activity of huwentoxin-IV are identified. Conclusion: Toxin activity involves a hydrophobic protrusion surrounded by a ring of basic residues. Significance: New structure-function information may provide a foundation for the design of peptides with therapeutic potential.

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“…Nooren et al [23] studied the composition of interacting residues and revealed existing different tendency between those residues from different type of protein complexes. It is suggested that amino acid physicochemical properties may also promote the prediction of binding residues [24-27]. Furthermore, many structural characteristics related to identification of critical residues have been intensively investigated, such as the secondary structure information etc.…”

Section: Introductionmentioning

confidence: 99%

Predicting protein-ATP binding sites from primary sequence through fusing bi-profile sampling of multi-view features

Zhang

et al. 2012

BMC Bioinformatics

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BackgroundAdenosine-5′-triphosphate (ATP) is one of multifunctional nucleotides and plays an important role in cell biology as a coenzyme interacting with proteins. Revealing the binding sites between protein and ATP is significantly important to understand the functionality of the proteins and the mechanisms of protein-ATP complex.ResultsIn this paper, we propose a novel framework for predicting the proteins’ functional residues, through which they can bind with ATP molecules. The new prediction protocol is achieved by combination of sequence evolutional information and bi-profile sampling of multi-view sequential features and the sequence derived structural features. The hypothesis for this strategy is single-view feature can only represent partial target’s knowledge and multiple sources of descriptors can be complementary.ConclusionsPrediction performances evaluated by both 5-fold and leave-one-out jackknife cross-validation tests on two benchmark datasets consisting of 168 and 227 non-homologous ATP binding proteins respectively demonstrate the efficacy of the proposed protocol. Our experimental results also reveal that the residue structural characteristics of real protein-ATP binding sites are significant different from those normal ones, for example the binding residues do not show high solvent accessibility propensities, and the bindings prefer to occur at the conjoint points between different secondary structure segments. Furthermore, results also show that performance is affected by the imbalanced training datasets by testing multiple ratios between positive and negative samples in the experiments. Increasing the dataset scale is also demonstrated useful for improving the prediction performances.

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Predicting protein interaction sites: binding hot-spots in protein–protein and protein–ligand interfaces

Cited by 151 publications

References 54 publications

Two Conserved Residues Govern the Salt and pH Dependencies of the Binding Reaction of a PDZ Domain

Two Conserved Residues Govern the Salt and pH Dependencies of the Binding Reaction of a PDZ Domain

Analysis of the Structural and Molecular Basis of Voltage-sensitive Sodium Channel Inhibition by the Spider Toxin Huwentoxin-IV (μ-TRTX-Hh2a)

Predicting protein-ATP binding sites from primary sequence through fusing bi-profile sampling of multi-view features

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