1d5q
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(New page: 200px<br /> <applet load="1d5q" size="450" color="white" frame="true" align="right" spinBox="true" caption="1d5q" /> '''SOLUTION STRUCTURE OF A MINI-PROTEIN REPROD...)
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Revision as of 11:52, 8 November 2007
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SOLUTION STRUCTURE OF A MINI-PROTEIN REPRODUCING THE CORE OF THE CD4 SURFACE INTERACTING WITH THE HIV-1 ENVELOPE GLYCOPROTEIN
Overview
Protein-protein interacting surfaces are usually large and intricate, making the rational design of small mimetics of these interfaces a, daunting problem. On the basis of a structural similarity between the, CDR2-like loop of CD4 and the beta-hairpin region of a short scorpion, toxin, scyllatoxin, we transferred the side chains of nine residues of, CD4, central in the binding to HIV-1 envelope glycoprotein (gp120), to a, structurally homologous region of the scorpion toxin scaffold. In, competition experiments, the resulting 27-amino acid miniprotein inhibited, binding of CD4 to gp120 with a 40 microM IC(50). Structural analysis by, NMR showed that both the backbone of the chimeric beta-hairpin and the, introduced side chains adopted conformations similar to those of the, parent CD4. Systematic single mutations suggested that most CD4 residues, from the CDR2-like loop were reproduced in the miniprotein, including the, critical Phe-43. The structural and functional analysis performed, suggested five additional mutations that, once incorporated in the, miniprotein, increased its affinity for gp120 by 100-fold to an IC(50) of, 0.1-1.0 microM, depending on viral strains. The resulting mini-CD4, inhibited infection of CD4(+) cells by different virus isolates. Thus, core regions of large protein-protein interfaces can be reproduced in, miniprotein scaffolds, offering possibilities for the development of, inhibitors of protein-protein interactions that may represent useful tools, in biology and in drug discovery.
About this Structure
1D5Q is a Protein complex structure of sequences from [1]. Full crystallographic information is available from OCA.
Reference
Rational engineering of a miniprotein that reproduces the core of the CD4 site interacting with HIV-1 envelope glycoprotein., Vita C, Drakopoulou E, Vizzavona J, Rochette S, Martin L, Menez A, Roumestand C, Yang YS, Ylisastigui L, Benjouad A, Gluckman JC, Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13091-6. PMID:10557278
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