2xht | pdb_00002xht

Structure of HSP90 with small molecule inhibitor bound

spinqualitylabelsall models 2xht, resolution 2.27Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2xht is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: C0Y Related: 2cdd, 1yes, 1uy9, 1byq, 2bsm, 1osf, 2wi3, 1uy8, 2bug, 2wi4, 2uwd, 2wi7, 2bt0, 1yer, 2xdu, 1uyg, 2ccu, 2bz5, 2xds, 2xdx, 2ccs, 1yc3, 1uyi, 1uyf, 1uyd, 2byi, 2xdl, 2wi2, 2vci, 1uy6, 2wi1, 2vcj, 1yc4, 2c2l, 2fwz, 2xdk, 1uyk, 1uyh, 2cct, 2fwy, 1uye, 1uyl, 2wi6, 2xab, 1yc1, 1uy7, 1uyc, 1yet, 2jjc, 2byh, 2wi5, 2xhr, 2xhx Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [HS90A_HUMAN] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. 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. 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 PubMed Inhibitors of the chaperone Hsp90 are potentially useful as chemotherapeutic agents in cancer. This paper describes an application of fragment screening to Hsp90 using a combination of NMR and high throughput X-ray crystallography. The screening identified an aminopyrimidine with affinity in the high micromolar range and subsequent structure-based design allowed its optimization into a low nanomolar series with good ligand efficiency. A phenolic chemotype was also identified in fragment screening and was found to bind with affinity close to 1 mM. This fragment was optimized using structure based design into a resorcinol lead which has subnanomolar affinity for Hsp90, excellent cell potency, and good ligand efficiency. This fragment to lead campaign improved affinity for Hsp90 by over 1,000,000-fold with the addition of only six heavy atoms. The companion paper (DOI: 10.1021/jm100060b) describes how the resorcinol lead was optimized into a compound that is now in clinical trials for the treatment of cancer. Fragment-based drug discovery applied to hsp90. Discovery of two lead series with high ligand efficiency.,Murray CW, Carr MG, Callaghan O, Chessari G, Congreve M, Cowan S, Coyle JE, Downham R, Figueroa E, Frederickson M, Graham B, McMenamin R, O'Brien MA, Patel S, Phillips TR, Williams G, Woodhead AJ, Woolford AJ J Med Chem. 2010 Aug 26;53(16):5942-55. PMID:20718493 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Heat Shock Protein structures

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