2QF6

HSP90 complexed with A56322

2QF6 の概要

• エントリーDOI: 10.2210/pdb2qf6/pdb
• 分子名称: Heat shock protein HSP 90-alpha, 6-(3-BROMO-2-NAPHTHYL)-1,3,5-TRIAZINE-2,4-DIAMINE (3 entities in total)
• 機能のキーワード: protein-inhibitor complex, chaperone
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P07900
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 93857.62

構造登録者

Park, C.H. (登録日: 2007-06-26, 公開日: 2008-07-01, 最終更新日: 2023-08-30)

主引用文献

Huth, J.R.,Park, C.,Petros, A.M.,Kunzer, A.R.,Wendt, M.D.,Wang, X.,Lynch, C.L.,Mack, J.C.,Swift, K.M.,Judge, R.A.,Chen, J.,Richardson, P.L.,Jin, S.,Tahir, S.K.,Matayoshi, E.D.,Dorwin, S.A.,Ladror, U.S.,Severin, J.M.,Walter, K.A.,Bartley, D.M.,Fesik, S.W.,Elmore, S.W.,Hajduk, P.J.
Discovery and design of novel HSP90 inhibitors using multiple fragment-based design strategies.
Chem.Biol.Drug Des., 70:1-12, 2007

PubMed Abstract: The molecular chaperone HSP90 has been shown to facilitate cancer cell survival by stabilizing key proteins responsible for a malignant phenotype. We report here the results of parallel fragment-based drug design approaches in the design of novel HSP90 inhibitors. Initial aminopyrimidine leads were elaborated using high-throughput organic synthesis to yield nanomolar inhibitors of the enzyme. Second site leads were also identified which bound to HSP90 in two distinct conformations, an 'open' and 'closed' form. Intriguingly, linked fragment approaches targeting both of these conformations were successful in producing novel, micromolar inhibitors. Overall, this study shows that, with only a few fragment hits, multiple lead series can be generated for HSP90 due to the inherent flexibility of the active site. Thus, ample opportunities exist to use these lead series in the development of clinically useful HSP90 inhibitors for the treatment of cancers.

PubMed: 17630989
DOI: 10.1111/j.1747-0285.2007.00535.x

実験手法

X-RAY DIFFRACTION (3.1 Å)