4l8z

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of Human Hsp90 with RL1

Structural highlights

4l8z is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.703Å
Ligands:
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

Heat shock protein 90 (HSP90) is a molecular chaperone to fold and maintain the proper conformation of many signaling proteins, especially some oncogenic proteins and mutated unstable proteins. Inhibition of HSP90 was recognized as an effective approach to simultaneously suppress several aberrant signaling pathways, and therefore it was considered as a novel target for cancer therapy. Here, by integrating several techniques including the fragment-based drug discovery method, fragment merging, computer aided inhibitor optimization, and structure-based drug design, we were able to identify a series of HSP90 inhibitors. Among them, inhibitors 13, 32, 36 and 40 can inhibit HSP90 with IC50 about 20-40 nM, which is at least 200-fold more potent than initial fragments in the protein binding assay. These new HSP90 inhibitors not only explore interactions with an under-studied subpocket, also offer new chemotypes for the development of novel HSP90 inhibitors as anticancer drugs.

Identification of a new series of potent diphenol HSP90 inhibitors by fragment merging and structure-based optimization.,Ren J, Li J, Wang Y, Chen W, Shen A, Liu H, Chen D, Cao D, Li Y, Zhang N, Xu Y, Geng M, He J, Xiong B, Shen J Bioorg Med Chem Lett. 2014 Jun 1;24(11):2525-9. doi: 10.1016/j.bmcl.2014.03.100. , Epub 2014 Apr 8. PMID:24751441^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ Ren J, Li J, Wang Y, Chen W, Shen A, Liu H, Chen D, Cao D, Li Y, Zhang N, Xu Y, Geng M, He J, Xiong B, Shen J. Identification of a new series of potent diphenol HSP90 inhibitors by fragment merging and structure-based optimization. Bioorg Med Chem Lett. 2014 Jun 1;24(11):2525-9. doi: 10.1016/j.bmcl.2014.03.100. , Epub 2014 Apr 8. PMID:24751441 doi:http://dx.doi.org/10.1016/j.bmcl.2014.03.100

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4l8z"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4l8z]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4L8Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4L8Z FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=RL1:[5-(6-BROMO[1,2,4]TRIAZOLO[4,3-A]PYRIDIN-3-YL)-2,4-DIHYDROXYPHENYL](3,4-DIHYDROISOQUINOLIN-2(1H)-YL)METHANONE'>RL1</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.703&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=RL1:[5-(6-BROMO[1,2,4]TRIAZOLO[4,3-A]PYRIDIN-3-YL)-2,4-DIHYDROXYPHENYL](3,4-DIHYDROISOQUINOLIN-2(1H)-YL)METHANONE'>RL1</scene></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4l8z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l8z OCA], [https://pdbe.org/4l8z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4l8z RCSB], [https://www.ebi.ac.uk/pdbsum/4l8z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4l8z ProSAT]</span></td></tr>
 </table>

4l8z

From Proteopedia

Current revision

Crystal structure of Human Hsp90 with RL1

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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