3RLR

Co-crystal structure of the HSP90 ATP binding domain in complex with 4-(2,4-dichloro-5-methoxyphenyl)-2,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

Summary for 3RLR

• Entry DOI: 10.2210/pdb3rlr/pdb
• Related: 3RLP 3RLQ
• Descriptor: Heat shock protein HSP 90-alpha, 4-(2,4-dichloro-5-methoxyphenyl)-2,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: chaperone
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P07900
• Total number of polymer chains: 2
• Total formula weight: 51955.07

Authors

Kung, P.-P.,Sinnema, P.-J.,Richardson, P.,Hickey, M.J.,Gajiwala, K.S.,Wang, F.,Huang, B.,McClellan, G.,Wang, J.,Maegley, K.,Bergqvist, S.,Mehta, P.P.,Kania, R. (deposition date: 2011-04-20, release date: 2011-06-08, Last modification date: 2024-02-28)

Primary citation

Kung, P.P.,Sinnema, P.J.,Richardson, P.,Hickey, M.J.,Gajiwala, K.S.,Wang, F.,Huang, B.,McClellan, G.,Wang, J.,Maegley, K.,Bergqvist, S.,Mehta, P.P.,Kania, R.
Design strategies to target crystallographic waters applied to the Hsp90 molecular chaperone.
Bioorg.Med.Chem.Lett., 21:3557-3562, 2011

PubMed Abstract: A series of novel and potent small molecule Hsp90 inhibitors was optimized using X-ray crystal structures. These compounds bind in a deep pocket of the Hsp90 enzyme that is partially comprised by residues Asn51 and Ser52. Displacement of several water molecules observed crystallographically in this pocket using rule-based strategies led to significant improvements in inhibitor potency. An optimized inhibitor (compound 17) exhibited potent Hsp90 inhibition in ITC, biochemical, and cell-based assays (K(d)=1.3 nM, K(i)=15 nM, and cellular IC(50)=0.5 μM).

PubMed: 21612924
DOI: 10.1016/j.bmcl.2011.04.130

Experimental method

X-RAY DIFFRACTION (1.7 Å)