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4lwg

From Proteopedia

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Current revision

Crystal Structure of the human Hsp90-alpha N-domain bound to the hsp90 inhibitor FJ4

Structural highlights

4lwg 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 1.599Å
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

HSP90 is ubiquitously overexpressed in a broad spectrum of human cancers and has been recognized as an attractive target for cancer treatment. Here, we described the fragment screening, synthesis and structure-activity relationship studies of small molecule inhibitors with 4,5-diarylisoxazole scaffold targeting HSP90. Among them, the compound N-(3-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4-morpholinopiperidin-1-yl)methyl)p henyl)isoxazol-5-yl)cyclopropanecarboxamide (108) showed high affinity for binding to HSP90 (FP binding assay, IC50 = 0.030 muM) and inhibited the proliferation of various human cancer cell lines with averaging GI50 about 88 nM. Compound 108 exhibited its functional inhibition of HSP90 by depleting key signaling pathways and concomitantly elevating of HSP70 and HSP27 in U-87MG cells. Further in vivo studies showed that compound 108 strongly suppressed the tumor growth of human glioblastoma xenograft model U-87MG with T/C = 18.35% at 50 mg/kg q3w/2.5w. Moreover, compound 108 also exhibited good pharmacokinetic properties. Together, our study implicates that compound 108 is a promising candidate of HSP90 inhibitor and is currently advanced to preclinical study.

Discovery of potent N-(isoxazol-5-yl)amides as HSP90 inhibitors.,Chen D, Shen A, Li J, Shi F, Chen W, Ren J, Liu H, Xu Y, Wang X, Yang X, Sun Y, Yang M, He J, Wang Y, Zhang L, Huang M, Geng M, Xiong B, Shen J Eur J Med Chem. 2014 Nov 24;87:765-81. doi: 10.1016/j.ejmech.2014.09.065. Epub, 2014 Sep 22. PMID:25313505^[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
↑ Chen D, Shen A, Li J, Shi F, Chen W, Ren J, Liu H, Xu Y, Wang X, Yang X, Sun Y, Yang M, He J, Wang Y, Zhang L, Huang M, Geng M, Xiong B, Shen J. Discovery of potent N-(isoxazol-5-yl)amides as HSP90 inhibitors. Eur J Med Chem. 2014 Nov 24;87:765-81. doi: 10.1016/j.ejmech.2014.09.065. Epub, 2014 Sep 22. PMID:25313505 doi:http://dx.doi.org/10.1016/j.ejmech.2014.09.065

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/4lwg"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4lwg]] 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=4LWG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4LWG FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FJ4:1-(5-CHLORO-2,4-DIHYDROXYPHENYL)-2-(4-METHOXYPHENYL)ETHANONE'>FJ4</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]] 1.599&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FJ4:1-(5-CHLORO-2,4-DIHYDROXYPHENYL)-2-(4-METHOXYPHENYL)ETHANONE'>FJ4</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=4lwg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lwg OCA], [https://pdbe.org/4lwg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4lwg RCSB], [https://www.ebi.ac.uk/pdbsum/4lwg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4lwg ProSAT]</span></td></tr>
 </table>

4lwg

From Proteopedia

Current revision

Crystal Structure of the human Hsp90-alpha N-domain bound to the hsp90 inhibitor FJ4

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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