| Structural highlights
2yk2 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: | , |
| Related: | 2h55, 2yi0, 2bsm, 1osf, 2wi3, 2ye4, 2yi5, 2ye5, 2bz5, 2yei, 2ccs, 2yeg, 1uyf, 1uyi, 1yc3, 2byi, 2ye3, 2yi6, 2vci, 2wi1, 2xjx, 2xdk, 2fwz, 1uyh, 2xjg, 2fwy, 1uyl, 1uye, 2xab, 2yeh, 2xht, 1uy7, 2xhr, 2yef, 2byh, 2wi5, 1uy9, 1yes, 2cdd, 1byq, 2yi7, 1uy8, 2wi4, 2bug, 2uwd, 2ye7, 2yeb, 2wi7, 2xhx, 2bt0, 2yej, 1yer, 2yec, 2xdu, 1uyg, 2ccu, 2xds, 2xdx, 2xk2, 2xjj, 1uyd, 2xdl, 2wi2, 2yee, 1uy6, 2ye2, 2vcj, 1yc4, 2ye9, 2c2l, 1uyk, 2cct, 2wi6, 1yc1, 2yea, 2ye6, 2yed, 1uyc, 1yet, 2jjc, 2ye8, 2yjw, 2yjx |
| 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.[1] [2]
Publication Abstract from PubMed
A novel class of heat shock protein 90 (Hsp90) inhibitors was developed after a low throughput screen (LTS) of a focused library containing approximately 21K compounds selected by virtual screening. The initial [1-{3-H-imidazo[4-5-c]pyridin-2-yl}-3,4-dihydro-2H-pyrido[2,1-a]isoindole- 6-one] (1) compound showed moderate activity (IC(50) = 7.6 muM on Hsp82, the yeast homologue of Hsp90). A high-resolution X-ray structure shows that compound 1 binds into an "induced" hydrophobic pocket, 10-15 A away from the ATP/resorcinol binding site. Iterative cycles of structure-based drug design (SBDD) and chemical synthesis led to the design and preparation of analogues with improved affinity. These optimized molecules make productive interactions within the ATP binding site as reported by other Hsp90 inhibitors. This resulted in compound 8, which is a highly potent inhibitor in biochemical and cellular assays (K(d) = 0.35 nM on Hsp90; IC(50) = 30 nM on SKBr3 mammary carcinoma cells) and in an in vivo leukemia model.
Tricyclic Series of Heat Shock Protein 90 (Hsp90) Inhibitors Part I: Discovery of Tricyclic Imidazo[4,5-c]pyridines as Potent Inhibitors of the Hsp90 Molecular Chaperone.,Vallee F, Carrez C, Pilorge F, Dupuy A, Parent A, Bertin L, Thompson F, Ferrari P, Fassy F, Lamberton A, Thomas A, Arrebola R, Guerif S, Rohaut A, Certal V, Ruxer JM, Delorme C, Jouanen A, Dumas J, Grepin C, Combeau C, Goulaouic H, Dereu N, Mikol V, Mailliet P, Minoux H J Med Chem. 2011 Oct 27;54(20):7206-19. Epub 2011 Oct 5. PMID:21972823[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Martinez-Ruiz A, Villanueva L, Gonzalez de Orduna C, Lopez-Ferrer D, Higueras MA, Tarin C, Rodriguez-Crespo I, Vazquez J, Lamas S. S-nitrosylation of Hsp90 promotes the inhibition of its ATPase and endothelial nitric oxide synthase regulatory activities. Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8525-30. Epub 2005 Jun 3. PMID:15937123 doi:10.1073/pnas.0407294102
- ↑ Forsythe HL, Jarvis JL, Turner JW, Elmore LW, Holt SE. Stable association of hsp90 and p23, but Not hsp70, with active human telomerase. J Biol Chem. 2001 May 11;276(19):15571-4. Epub 2001 Mar 23. PMID:11274138 doi:10.1074/jbc.C100055200
- ↑ Vallee F, Carrez C, Pilorge F, Dupuy A, Parent A, Bertin L, Thompson F, Ferrari P, Fassy F, Lamberton A, Thomas A, Arrebola R, Guerif S, Rohaut A, Certal V, Ruxer JM, Delorme C, Jouanen A, Dumas J, Grepin C, Combeau C, Goulaouic H, Dereu N, Mikol V, Mailliet P, Minoux H. Tricyclic Series of Heat Shock Protein 90 (Hsp90) Inhibitors Part I: Discovery of Tricyclic Imidazo[4,5-c]pyridines as Potent Inhibitors of the Hsp90 Molecular Chaperone. J Med Chem. 2011 Oct 27;54(20):7206-19. Epub 2011 Oct 5. PMID:21972823 doi:10.1021/jm200784m
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