Strategy for analysing the co-operativity of intramolecular interactions in peptides and proteins

Horovitz, Amnon; Fersht, Alan R.

doi:10.1016/0022-2836(90)90275-q

Cited by 328 publications

(345 citation statements)

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“…The method was developed to deconvolute the thermodynamics of a system and to relate these to available structural information (15,28). However, it has been recognized that DMC data also can serve to indicate structural proximity (22,23).…”

Section: Discussionmentioning

confidence: 99%

“…Most of these methods do not provide the relative orientation of the two proteins, but only the location of the binding sites. This problem can be solved by using a more advanced procedure for mutagenesis, in which pairs of residues (X and Y located on proteins E 1 and E 2 , respectively) are mutated both singly and doubly, allowing the construction of a double-mutant cycle (DMC) (14,15). Assuming that only neighboring residues interact, this method can be used to identify distance constraints between the two proteins.…”

mentioning

confidence: 99%

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Structure of the interferon-receptor complex determined by distance constraints from double-mutant cycles and flexible docking

Roisman

Piehler

Trosset

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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The pleiotropic activity of type I interferons has been attributed to the specific interaction of IFN with the cell-surface receptor components ifnar1 and ifnar2. To date, the structure of IFN has been solved, but not that of the receptor or the complex. In this study, the structure of the IFN-␣2-ifnar2 complex was generated with a docking procedure, using nuclear Overhauser effect-like distance constraints obtained from double-mutant cycle experiments. The interaction free energy between 13 residues of the ligand and 11 of the receptor was measured by double-mutant cycles. Of the 100 pairwise interactions probed, five pairs of residues were found to interact. These five interactions were incorporated as distance constraints into the flexible docking program PRODOCK by using fixed and movable energy-gradient grids attached to the receptor and ligand, respectively. Multistart minimization and Monte Carlo minimization docking of IFN-␣2 onto ifnar2 converged to a welldefined average structure, with the five distance constraints being satisfied. Furthermore, no structural artifacts or intraloop energy strain were observed. The mutual binding sites on IFN-␣2 and ifnar2 predicted from the model showed an almost complete superposition with the ones determined from mutagenesis studies. Based on this structure, differences in IFN-␣2 versus IFN-␤ binding are discussed.protein-protein interaction ͉ PRODOCK ͉ Monte Carlo minimization ͉ grids T ype I interferons (IFNs) are a family of homologous cytokines that potently elicit an antiviral and antiproliferative state in cells. All human type I IFNs (IFN-␣, -␤, and -) bind to a cell surface receptor consisting of two transmembrane proteins, type I IFN receptor (ifnar) 1 (1) and ifnar2 (2), which associate upon binding. IFN binds with high affinity to ifnar2, probably recruiting ifnar1 subsequently. Type I IFNs belong to the class of helical cytokines and are built of five helices. The structures of human IFN-␣2 (3) and IFN-␤ have been resolved (4). The receptor structures are unknown, but can be modeled by homology to human cytokine receptors with known structures such as tissue factor (5) and IFN-␥ receptor (6). Mutational studies have revealed the mutual binding sites on IFN-␣2 and ifnar2. On IFN-␣2, ifnar2 binds to the A helix (residues 12-15), the AB loop (residues 26-35), and the E helix (residues 144-153) (7), whereas on ifnar2, IFN-␣2 binds to three loops of the N-terminal domain of the receptor (residues 45-52, 75-82, and 102-106) with no significant binding detected toward the Cterminal domain (8-10). Determination of the receptor-ligand structure will significantly promote our understanding of IFN signaling at the molecular level.Docking of protein complexes, and calculating the conformational changes that occur at the binding interface, is a computational challenge. Rigid protein docking software algorithms are fast and can be used to dock two proteins for which the NMR or x-ray structures have been solved independently (11, 12). However, successful docking relies o...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Structure of the interferon-receptor complex determined by distance constraints from double-mutant cycles and flexible docking

Roisman

Piehler

Trosset

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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“…To assess energetic coupling between Glu-79 and Glu-416, we conducted double mutant cycle analysis (23,24). The coupling coefficient, ⍀, is defined as in Equation 3,…”

Section: Glu-79 and Glu-416 Contribute To Protonmentioning

confidence: 99%

Gating Transitions in the Palm Domain of ASIC1a*

Vecchia

Rued

Carattino

2013

Journal of Biological Chemistry

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Background: Extracellular acidification promotes structural rearrangements in the ectodomain of ASIC1a that result in activation and desensitization. Results: Glu-79 and Glu-416 cooperatively facilitate proton gating. The lower palm domain contracts upon extracellular acidification. Conclusion:The lower palm domain mediates conformational changes that drive pore opening and closing events. Significance: This study provides insight into the molecular mechanism of gating of epithelial sodium/degenerin channels.

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“…⌬ 4 G (i,j),(k,l) is measured by using a four-dimensional thermodynamic construct, most easily represented as a double-mutant cycle of double-mutant cycles (17). Fig.…”

Section: Allostericmentioning

confidence: 99%

“…Through double-mutant cycle analysis (Fig. 1B) (16)(17)(18), it was shown that residues along this pathway are energetically coupled, implying that the allosteric pathway connecting the activation gate and selectivity filter can be described as a trajectory of energetic connectivity, in accord with the mechanical view of signal propagation presented by Ranganathan and colleagues (4,5,19). Now, we apply high-order thermodynamic coupling analysis of voltage-dependent gating of the Kv channel, serving as a model system, to unravel the mechanism underlying experimentally determined features of energy transduction along allosteric communication trajectories.…”

mentioning

confidence: 99%

Principles underlying energetic coupling along an allosteric communication trajectory of a voltage-activated K ⁺ channel

Sadovsky

Yifrach²

2007

Proc. Natl. Acad. Sci. U.S.A.

119

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The information flow between distal elements of a protein may rely on allosteric communication trajectories lying along the protein's tertiary or quaternary structure. To unravel the underlying features of energy parsing along allosteric pathways in voltagegated K ؉ channels, high-order thermodynamic coupling analysis was performed. We report that such allosteric trajectories are functionally conserved and delineated by well defined boundaries. Moreover, allosteric trajectories assume a hierarchical organization whereby increasingly stronger layers of cooperative residue interactions act to ensure efficient and cooperative long-range coupling between distal channel regions. Such long-range communication is brought about by a coupling of local and global conformational changes, suggesting that the allosteric trajectory also corresponds to a pathway of physical deformation. Supported by theoretical analyses and analogy to studies analyzing the contribution of long-range residue coupling to protein stability, we propose that such experimentally derived trajectory features are a general property of allosterically regulated proteins.is a fundamental property of many allosteric proteins. Information transfer between such elements may be achieved by propagation of conformational changes through a protein structure, induced by changes in chemical or electrical potential. However, while the structures of stable conformational states of several allosteric proteins are known, the mechanism(s) by which ligand-induced structural changes propagate through the molecule remains elusive. In the absence of extensive experimental data accurately describing such allosteric networks, computational analyses have attempted to provide mechanistic explanations for long-range coupling in proteins. Structure-based computer simulations suggest that conformational changes may propagate signal transmission by a redistribution of native-state conformational ensembles (1-3). Others suggest that conformational changes may propagate by simple mechanical deformation of the protein structure along pathways of energetic connectivity, comprising adjacent amino acid positions in the tertiary structure (4, 5). Conformational changes are central to the function of voltage-activated potassium channels (Kv), poreforming proteins that open and close in response to changes in membrane potential. Such conformational transitions regulate the flow of potassium ions across the membrane (6-9), a process underlying many fundamental biological processes, in particular the generation of nerve and muscle action potentials (10). These conformational changes, moreover, play a fundamental role in mediating coupling between the voltage-sensor, activation gate and selectivity filter elements of Kv channels (6)(7)(8)(9)(11)(12)(13)(14).Amenable to rapid and highly accurate functional characterization without the need for protein purification, the Kv channel represents an excellent model for studying the features underlying allosteric communication networks in proteins. R...

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Strategy for analysing the co-operativity of intramolecular interactions in peptides and proteins

Cited by 328 publications

References 9 publications

Structure of the interferon-receptor complex determined by distance constraints from double-mutant cycles and flexible docking

Structure of the interferon-receptor complex determined by distance constraints from double-mutant cycles and flexible docking

Gating Transitions in the Palm Domain of ASIC1a*

Principles underlying energetic coupling along an allosteric communication trajectory of a voltage-activated K ⁺ channel

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Strategy for analysing the co-operativity of intramolecular interactions in peptides and proteins

Cited by 328 publications

References 9 publications

Structure of the interferon-receptor complex determined by distance constraints from double-mutant cycles and flexible docking

Structure of the interferon-receptor complex determined by distance constraints from double-mutant cycles and flexible docking

Gating Transitions in the Palm Domain of ASIC1a*

Principles underlying energetic coupling along an allosteric communication trajectory of a voltage-activated K + channel

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Principles underlying energetic coupling along an allosteric communication trajectory of a voltage-activated K ⁺ channel