PMID: 8939700Oct 1, 1996Paper

Probing the chemical basis of binding activity in an SH3 domain by protein signature analysis

Chemistry & Biology
T W MuirS B Kent

Abstract

Modifying the covalent structure of a protein is an effective empirical route to probing three-dimensional structure and biological function. Here we describe a combinatorial protein chemistry strategy for studying structure-activity relationships in proteins. Our approach (termed 'protein signature analysis') involves functional selection from an array of self-encoded protein analogs prepared by total synthesis, coupled to a simple chemical readout that unambiguously identifies the modified proteins in the resulting active and inactive populations. Protein signature analysis was used to study the interaction of the amino-terminal SH3 domain from the cellular adaptor protein c-Crk with its cognate proline-rich peptide, C3G. Using a functional selection assay, the qualitative effects of scanning a series of synthetic analog units through the amino-acid sequence of the SH3 domain were evaluated. The analog units were designed to alter both amino-acid sidechains and the polypeptide backbone within the protein. These chemical studies revealed that the sidechain of Asp 150 in the SH3 domain is essential for ligand binding and that changes in the structure of the polypeptide backbone can also result in loss of binding activity. These...Continue Reading

References

May 1, 1992·Bioconjugate Chemistry·H F GaertnerR E Offord
Sep 1, 1992·International Journal of Peptide and Protein Research·M SchnölzerS B Kent
Jun 26, 1992·Science·D MendelP G Schultz
Jul 27, 1990·Science·J K Scott, G P Smith
Oct 1, 1995·Nature Structural Biology·A R DavidsonR T Sauer
Aug 1, 1995·Current Opinion in Biotechnology·D Shortle, J Sondek
Aug 1, 1993·Current Opinion in Biotechnology·T W Muir, S B Kent
Nov 4, 1994·Science·P E DawsonS B Kent
Jul 5, 1994·Proceedings of the National Academy of Sciences of the United States of America·C F Liu, J P Tam
Oct 1, 1993·Science·B T ChaitS B Kent
Dec 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·M Baca, S B Kent
Jul 1, 1993·Protein Science : a Publication of the Protein Society·M BacaS B Kent
Apr 30, 1996·Proceedings of the National Academy of Sciences of the United States of America·Y ZhaoB T Chait
Jul 1, 1993·Current Biology : CB·T Pawson, J Schlessingert

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Citations

Aug 28, 1998·Current Opinion in Biotechnology·J Wilken, S B Kent
Apr 26, 2000·Chemistry & Biology·R L Winston, J M Gottesfeld
Oct 24, 1997·Nature·K SeverinM R Ghadiri
Oct 14, 2003·Journal of Peptide Science : an Official Publication of the European Peptide Society·Stephen Kent
Apr 29, 1998·The Journal of Peptide Research : Official Journal of the American Peptide Society·J A CamareroT W Muir
Jul 1, 1997·Mass Spectrometry Reviews·R L Winston, M C Fitzgerald
Sep 2, 2011·Bioorganic & Medicinal Chemistry·Geoffray LericheAlain Wagner

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