1d5q
From Proteopedia
(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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'''SOLUTION STRUCTURE OF A MINI-PROTEIN REPRODUCING THE CORE OF THE CD4 SURFACE INTERACTING WITH THE HIV-1 ENVELOPE GLYCOPROTEIN'''<br /> | '''SOLUTION STRUCTURE OF A MINI-PROTEIN REPRODUCING THE CORE OF THE CD4 SURFACE INTERACTING WITH THE HIV-1 ENVELOPE GLYCOPROTEIN'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Protein-protein interacting surfaces are usually large and intricate, making the rational design of small mimetics of these interfaces a | + | 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== | ==About this Structure== | ||
| - | 1D5Q is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/ ]. Full crystallographic information is available from [http:// | + | 1D5Q is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/ ]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1D5Q OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Benjouad, A.]] | [[Category: Benjouad, A.]] | ||
[[Category: Drakopoulou, E.]] | [[Category: Drakopoulou, E.]] | ||
| - | [[Category: Gluckman, J | + | [[Category: Gluckman, J C.]] |
[[Category: Martin, L.]] | [[Category: Martin, L.]] | ||
[[Category: Menez, A.]] | [[Category: Menez, A.]] | ||
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[[Category: Vita, C.]] | [[Category: Vita, C.]] | ||
[[Category: Vizzanova, J.]] | [[Category: Vizzanova, J.]] | ||
| - | [[Category: Yang, Y | + | [[Category: Yang, Y S.]] |
[[Category: Ylisastigui, L.]] | [[Category: Ylisastigui, L.]] | ||
[[Category: alpha-beta structure]] | [[Category: alpha-beta structure]] | ||
[[Category: charybdotoxin-like motif]] | [[Category: charybdotoxin-like motif]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:13:17 2008'' |
Revision as of 10:13, 21 February 2008
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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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