1uyl

From Proteopedia

Revision as of 15:04, 15 February 2008

STRUCTURE-ACTIVITY RELATIONSHIPS IN PURINE-BASED INHIBITOR BINDING TO HSP90 ISOFORMS

Overview

Inhibition of the ATPase activity of the chaperone protein HSP90 is a, potential strategy for treatment of cancers. We have determined structures, of the HSP90alpha N-terminal domain complexed with the purine-based, inhibitor, PU3, and analogs with enhanced potency both in enzyme and, cell-based assays. The compounds induce upregulation of HSP70 and, downregulation of the known HSP90 client proteins Raf-1, CDK4, and ErbB2, confirming that the molecules inhibit cell growth by a mechanism dependent, on HSP90 inhibition. We have also determined the first structure of the, N-terminal domain of HSP90beta, complexed with PU3. The structures allow a, detailed rationale to be developed for the observed affinity of the PU3, class of compounds for HSP90 and also provide a structural framework for, design of compounds with improved binding affinity and drug-like, properties.

About this Structure

1UYL is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Structure-activity relationships in purine-based inhibitor binding to HSP90 isoforms., Wright L, Barril X, Dymock B, Sheridan L, Surgenor A, Beswick M, Drysdale M, Collier A, Massey A, Davies N, Fink A, Fromont C, Aherne W, Boxall K, Sharp S, Workman P, Hubbard RE, Chem Biol. 2004 Jun;11(6):775-85. PMID:15217611

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