2VW5

Structure Of The Hsp90 Inhibitor 7-O-carbamoylpremacbecin Bound To The N- Terminus Of Yeast Hsp90

Summary for 2VW5

• Entry DOI: 10.2210/pdb2vw5/pdb
• Related: 1A4H 1AH6 1AH8 1AM1 1AMW 1BGQ 1HK7 1US7 1USU 1USV 1ZW9 1ZWH 2AKP 2BRC 2BRE 2CG9 2CGE 2CGF 2IWS 2IWU 2IWX 2VLS
• Descriptor: ATP-DEPENDENT MOLECULAR CHAPERONE HSP82, (4E,8S,9R,10E,12S,13R,14S,16R)-13,20-dihydroxy-14-methoxy-4,8,10,12,16-pentamethyl-3-oxo-2-azabicyclo[16.3.1]docosa-1(22),4,10,18,20-pentaen-9-yl carbamate, SULFATE ION, ... (4 entities in total)
• Functional Keywords: atpase, cytoplasm, inhibitor, chaperone, atp-binding, stress response, nucleotide-binding
• Biological source: SACCHAROMYCES CEREVISIAE (BAKER'S YEAST)
• Cellular location: Cytoplasm: P02829
• Total number of polymer chains: 4
• Total formula weight: 99709.47

Authors

Roe, S.M.,Prodromou, C.,Pearl, L.H. (deposition date: 2008-06-16, release date: 2008-09-02, Last modification date: 2023-12-13)

Primary citation

Zhang, M.Q.,Gaisser, S.,Nur-E-Alam, M.,Sheehan, L.S.,Vousden, W.A.,Gaitatzis, N.,Peck, G.,Coates, N.J.,Moss, S.J.,Radzom, M.,Foster, T.A.,Sheridan, R.M.,Gregory, M.A.,Roe, S.M.,Prodromou, C.,Pearl, L.H.,Boyd, S.M.,Wilkinson, B.,Martin, C.J.
Optimizing Natural Products by Biosynthetic Engineering: Discovery of Nonquinone Hsp90 Inhibitors.
J.Med.Chem., 51:5494-, 2008

PubMed Abstract: A biosynthetic medicinal chemistry approach was applied to the optimization of the natural product Hsp90 inhibitor macbecin. By genetic engineering, mutants have been created to produce novel macbecin analogues including a nonquinone compound (5) that has significantly improved binding affinity to Hsp90 (Kd 3 nM vs 240 nM for macbecin) and reduced toxicity (MTD > or = 250 mg/kg). Structural flexibility may contribute to the preorganization of 5 to exist in solution in the Hsp90-bound conformation.

PubMed: 18800759
DOI: 10.1021/JM8006068

Experimental method

X-RAY DIFFRACTION (1.9 Å)