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Cited by 359

The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.

Protein-protein recognition: Crystal structural analysis of a barnase-barstar complex at 2.0-.ANG. resolution

Buckle, Ashley M., Schreiber, Gideon, Fersht, Alan R.·1994·Biochemistry
DOI 10.1021/bi00196a004
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Abstract

We have solved, refined, and analyzed the 2.0-å resolution crystal structure of a 1:1 complex between the bacterial ribonuclease, barnase, and a Cys-->Ala(40,82) double mutant of its intracellular polypeptide inhibitor, barstar. Barstar inhibits barnase by sterically blocking the active site with a helix and adjacent loop segment. Almost half of the 14 hydrogen bonds between barnase and barstar involve two charged residues, and a third involve one charged partner. The electrostatic contribution to the overall binding energy is considerably greater than for other protein-protein interactions. Consequently, the very high rate constant for the barnase-barstar association (10(8) s-1 M-1) is most likely due to electrostatic steering effects. The barnase active-site residue His102 is located in a pocket on the surface of barstar, and its hydrogen bonds with Asp39 and Gly31 residues of barstar are directly responsible for the pH dependence of barnase-barstar binding. There is a high degree of complementarity both of the shape and of the charge of the interacting surfaces, but neither is perfect. The surface complementarity is slightly poorer than in protease-inhibitor complexes but a little better than in antibody-antigen interactions. However, since the burial of solvent in the barnase-barstar interface improves the fit significantly by filling in the majority of gaps, as well as stabilizing unfavorable electrostatic interactions, its role seems to be more important than in other protein-protein complexes. The electrostatic interactions between barnase and barstar are very similar to those between barnase and the tetranucleotide d(CGAC). In the barnase-barstar complex, the two phosphate-binding sites in the barnase active site are occupied by Asp39 and Gly43 of barstar. However, barstar has no equivalent for a guanine base of an RNA substrate, resulting in the occupation of the guanine recognition site in the barnase-barstar complex by nine ordered water molecules. Upon barnase-barstar binding, entropy losses resulting from the immobilization of segments of the protein chain and the energetic costs of conformational changes are minimized due to the essentially preformed active site of barnase. However, a certain degree of flexibility within the barnase active site is required to allow for the structural differences between barnase-barstar binding and barnase-RNA binding. A comparison between the bound and the free barstar structure shows that the overall structural response to barnase-binding is significant. This response can be best described as outwardly oriented, rigid-body movements of the four alpha-helices of barstar, resulting in the structure of bound barstar being somewhat expanded.

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Metadata

Authors
Buckle, A. M., Schreiber, G., & Fersht, A. R.
Venue
Biochemistry
Publisher
American Chemical Society (ACS)
Published
1994-08-01
Volume
33
Issue
30
Pages
8878-8889
ISSN
  • 0006-2960 (ISSN-L)
  • 1520-4995
DOI
10.1021/bi00196a004
OpenAlex
W2171356751
Cited by
359
References
30
FWCI
3.19
Type
journal article
Language
en
Open access
closed

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