2vw5
From Proteopedia
STRUCTURE OF THE HSP90 INHIBITOR 7-O-CARBAMOYLPREMACBECIN BOUND TO THE N- TERMINUS OF YEAST HSP90
Structural highlights
Function[HSP82_YEAST] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. The nucleotide-free form of the dimer is found in an open conformation in which the N-termini are not dimerized and the complex is ready for client protein binding. Binding of ATP induces large conformational changes, resulting in the formation of a ring-like closed structure in which the N-terminal domains associate intramolecularly with the middle domain and also dimerize with each other, stimulating their intrinsic ATPase activity and acting as a clamp on the substrate. Finally, ATP hydrolysis results in the release of the substrate. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function. Required for growth at high temperatures.[1] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedA 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. Optimizing natural products by biosynthetic engineering: discovery of nonquinone Hsp90 inhibitors.,Zhang MQ, Gaisser S, Nur-E-Alam M, Sheehan LS, Vousden WA, Gaitatzis N, Peck G, Coates NJ, Moss SJ, Radzom M, Foster TA, Sheridan RM, Gregory MA, Roe SM, Prodromou C, Pearl L, Boyd SM, Wilkinson B, Martin CJ J Med Chem. 2008 Sep 25;51(18):5494-7. PMID:18800759[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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