Analysis of protein-protein interactions and the effects of amino acid mutations on their energetics. The importance of water molecules in the binding epitope

Covell, David G.; Wallqvist, Anders

doi:10.1006/jmbi.1997.1028

Cited by 74 publications

(53 citation statements)

References 50 publications

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“…1B buried on the side of XGD1-44, about 47% is caused by two patches that contribute to the direct interaction with X-bp. The remaining 53% is occupied by ordered water molecules, which form extensive water-mediated hydrogen bonds and may contribute to the stability of the two direct contacts, as observed in antigen-antibody interfaces (23). The hydrophilic patch is formed by a cluster of negatively charged Gla residues 25, 29, and 32, Arg28, and Ca-1, as shown in Fig.…”

Section: Resultsmentioning

confidence: 95%

Crystal structure of an anticoagulant protein in complex with the Gla domain of factor X

Mizuno

Fujimoto

Atoda

et al. 2001

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

132

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The ␥-carboxyglutamic acid (Gla) domain of blood coagulation factors is responsible for Ca 2؉ -dependent phospholipid membrane binding. Factor X-binding protein (X-bp), an anticoagulant protein from snake venom, specifically binds to the Gla domain of factor X. The crystal structure of X-bp in complex with the Gla domain peptide of factor X at 2.3-Å resolution showed that the anticoagulation is based on the fact that two patches of the Gla domain essential for membrane binding are buried in the complex formation. The Gla domain thus is expected to be a new target of anticoagulant drugs, and X-bp provides a basis for designing them. This structure also provides a membrane-bound model of factor X.

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Section: Resultsmentioning

confidence: 95%

Crystal structure of an anticoagulant protein in complex with the Gla domain of factor X

Mizuno

Fujimoto

Atoda

et al. 2001

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

132

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“…Whereas this might be an extreme case, at many proteinprotein interface amino acid side chains can be found that should have the potential to participate in binding, but in fact play no or only a very minor role (see examples summarized in Ref. 27).…”

Section: Discussionmentioning

confidence: 99%

Identification of the F1-binding Surface on the δ-Subunit of ATP Synthase

Weber

Wilke-Mounts

Senior

2003

Journal of Biological Chemistry

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The stator function in ATP synthase was studied by a combined mutagenesis and fluorescence approach. Specifically, binding of ␦-subunit to ␦-depleted F 1 was studied. A plausible binding surface on ␦-subunit was identified from conservation of amino acid sequence and the high resolution NMR structure. Specific mutations aimed at modulating binding were introduced onto this surface. Affinity of binding of wild-type and mutant ␦-subunits to ␦-depleted F 1 was determined quantitatively using the fluorescence signals of natural ␦-Trp-28, inserted ␦-Trp-11, or inserted ␦-Trp-79. The results demonstrate that helices 1 and 5 in the N-terminal domain of the ␦-subunit provide the F 1 -binding surface of ␦. Unexpectedly, mutations that impaired binding between F 1 and ␦ were found to not necessarily impair ATP synthase activity. Further investigation revealed that inclusion of the soluble cytoplasmic domain of the b subunit substantially enhanced affinity of binding of ␦-subunit to F 1 . The new data show that the stator is "overengineered" to resist rotor torque during catalysis.ATP synthase is the membrane enzyme responsible for ATP synthesis in oxidative and photophosphorylation of prokaryotes and eukaryotes, and also for ATP-driven proton pumping to generate the transmembrane proton gradient in bacterial membranes. In Escherichia coli, ATP synthase consists of a complex of eight subunits, ␣ 3 ␤ 3 ␥␦⑀ab 2 c n . It was defined in earlier times in terms of a membrane-peripheral F 1 sector (␣ 3 ␤ 3 ␥␦⑀) containing three catalytic sites, and a membrane-embedded F 0 sector (ab 2 c n ), which carries out transmembrane proton transport. Recent work has demonstrated that the enzyme functions as a rotary motor. The centrally located "rotor" consists of subunits ␥⑀c n . At the top, it rotates inside the ␣ 3 ␤ 3 hexagon, and thus modifies the activities of the catalytic sites; at the base, it rotates against subunit a, thereby facilitating proton movement. In this way, the energy of the proton gradient is transduced into the energy of ATP synthesis/hydrolysis. Understanding the mechanism by which this occurs is currently of major interest. To ensure that subunits a and ␣ 3 ␤ 3 remain firmly fixed in relation to each other they are connected by a peripheral structure, the "stator" stalk, consisting of subunits b 2 and ␦. For recent reviews of the structure and function of ATP synthase, see Refs. 1-3.The stator must be able to resist strain resulting from rotor torque, thus its construction is of considerable importance. The dimer of b-subunits forms an elongated helical connection between subunit a and the C-terminal domain of the ␦-subunit, it lies at one side of the ␣ 3 ␤ 3 hexagon, and its functional domains have been well characterized (4 -6). There may exist functional interactions between b 2 and the ␣ 3 ␤ 3 hexagon (7). Currently only partial high-resolution structure has been reported for the b subunit (8, 9). The ␦-subunit has been shown by electron microscopy to bind to the very top ("crown") of the ␣ 3 ␤ 3 hexagon (10),...

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“…Interface cores are enriched in aromatic and aliphatic residues and depleted in the charged residues Lys, Glu and Asp, but not Arg. Moreover, interface core residues are better conserved in evolution than the rest of the protein surface (Guharoy & Chakrabarti, 2005) and they constitute the majority of the 'hot spots' which strongly destabilize the assembly when substituted by mutation (Covell & Wallqvist, 1997;Bogan & Thorn, 1998;Guerois et al, 2002;Kortemme & Baker, 2002). Thus, interface cores resemble the protein interior except for the presence of Arg residues, which are as abundant at protein-protein interfaces, even in the core, as elsewhere on the protein surface.…”

Section: Permanent Assemblies Versus Transient Complexes: Interface Smentioning

confidence: 99%

Macromolecular recognition in the Protein Data Bank

Janin

Rodier

Chakrabarti

et al. 2006

Acta Crystallogr D Biol Cryst

101

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Crystal structures deposited in the Protein Data Bank illustrate the diversity of biological macromolecular recognition: transient interactions in protein-protein and protein-DNA complexes and permanent assemblies in homodimeric proteins. The geometric and physical chemical properties of the macromolecular interfaces that may govern the stability and specificity of recognition are explored in complexes and homodimers compared with crystal-packing interactions. It is found that crystal-packing interfaces are usually much smaller; they bury fewer atoms and are less tightly packed than in specific assemblies. Standard-size interfaces burying 1200-2000 Å 2 of protein surface occur in protease-inhibitor and antigen-antibody complexes that assemble with little or no conformation changes. Short-lived electron-transfer complexes have small interfaces; the larger size of the interfaces observed in complexes involved in signal transduction and homodimers correlates with the presence of conformation changes, often implicated in biological function. Results of the CAPRI (critical assessment of predicted interactions) blind prediction experiment show that docking algorithms efficiently and accurately predict the mode of assembly of proteins that do not change conformation when they associate. They perform less well in the presence of large conformation changes and the experiment stimulates the development of novel procedures that can handle such changes.

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Analysis of protein-protein interactions and the effects of amino acid mutations on their energetics. The importance of water molecules in the binding epitope

Cited by 74 publications

References 50 publications

Crystal structure of an anticoagulant protein in complex with the Gla domain of factor X

Crystal structure of an anticoagulant protein in complex with the Gla domain of factor X

Identification of the F1-binding Surface on the δ-Subunit of ATP Synthase

Macromolecular recognition in the Protein Data Bank

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