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4b7p

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Revision as of 00:24, 5 August 2016

Structure of HSP90 with NMS-E973 inhibitor bound

Structural highlights

4b7p 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:	1byq, 1osf, 1uy6, 1uy7, 1uy8, 1uy9, 1uyc, 1uyd, 1uye, 1uyf, 1uyg, 1uyh, 1uyi, 1uyk, 1uyl, 1yc1, 1yc3, 1yc4, 1yer, 1yes, 1yet, 2bsm, 2bt0, 2bug, 2byh, 2byi, 2bz5, 2c2l, 2ccs, 2cct, 2ccu, 2fwy, 2fwz, 2jjc, 2uwd, 2vci, 2vcj, 2wi1, 2wi2, 2wi3, 2wi4, 2wi5, 2wi6, 2wi7, 2xab, 2xdk, 2xdl, 2xds, 2xdu, 2xdx, 2xhr, 2xht, 2xhx, 2xjg, 2xjj, 2xjx, 2xk2, 2ye2, 2ye3, 2ye4, 2ye5, 2ye6, 2ye7, 2ye8, 2ye9, 2yea, 2yeb, 2yec, 2yed, 2yee, 2yef, 2yeg, 2yeh, 2yei, 2yej, 2yi0, 2yi5, 2yi6, 2yi7, 2yjw, 2yjx, 2yk2, 2yk9, 2ykb, 2ykc, 2yke, 2yki, 2ykj, 4aif, 4awo, 4awp, 4awq
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

PURPOSE: Recent developments of second generation Hsp90 inhibitors suggested a potential for development of this class of molecules also in tumors that have become resistant to molecular targeted agents. Disease progression is often due to brain metastases, sometimes related to insufficient drug concentrations within the brain. Our objective was to identify and characterize a novel inhibitor of Hsp90 able to cross the blood-brain barrier (BBB).EXPERIMENTAL DESIGN: Here is described a detailed biochemical and crystallographic characterization of NMS-E973. Mechanism-based anticancer activity was described in cell models, including models of resistance to kinase inhibitors. Pharmacokinetics properties were followed in plasma, tumor, liver, and brain. In vivo activity and pharmacodynamics, as well as the pharmacokinetic/pharmacodynamic relationships, were evaluated in xenografts, including an intracranially implanted melanoma model.RESULTS: NMS-E973, representative of a novel isoxazole-derived class of Hsp90 inhibitors, binds Hsp90alpha with subnanomolar affinity and high selectivity towards kinases, as well as other ATPases. It possesses potent antiproliferative activity against tumor cell lines and a favorable pharmacokinetic profile, with selective retention in tumor tissue and ability to cross the BBB. NMS-E973 induces tumor shrinkage in different human tumor xenografts, and is highly active in models of resistance to kinase inhibitors. Moreover, consistent with its brain penetration, NMS-E973 is active also in an intracranially implanted melanoma model.CONCLUSIONS: Overall, the efficacy profile of NMS-E973 suggests a potential for development in different clinical settings, including tumors that have become resistant to molecular targeted agents, particularly in cases of tumors which reside beyond the BBB. Clin Cancer Res; 1-13. (c)2013 AACR.

NMS-E973, a Novel Synthetic Inhibitor of Hsp90 with Activity against Multiple Models of Drug Resistance to Targeted Agents, Including Intracranial Metastases.,Fogliatto G, Gianellini L, Brasca MG, Casale E, Ballinari D, Ciomei M, Degrassi A, De Ponti A, Germani M, Guanci M, Paolucci M, Polucci P, Russo M, Sola F, Valsasina B, Visco C, Zuccotto F, Donati D, Felder E, Pesenti E, Galvani A, Mantegani S, Isacchi A Clin Cancer Res. 2013 Jun 5. PMID:23674492^[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
↑ Fogliatto G, Gianellini L, Brasca MG, Casale E, Ballinari D, Ciomei M, Degrassi A, De Ponti A, Germani M, Guanci M, Paolucci M, Polucci P, Russo M, Sola F, Valsasina B, Visco C, Zuccotto F, Donati D, Felder E, Pesenti E, Galvani A, Mantegani S, Isacchi A. NMS-E973, a Novel Synthetic Inhibitor of Hsp90 with Activity against Multiple Models of Drug Resistance to Targeted Agents, Including Intracranial Metastases. Clin Cancer Res. 2013 Jun 5. PMID:23674492 doi:10.1158/1078-0432.CCR-12-3512

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/4b7p"

@@ Line 1: / Line 1: @@
 ==Structure of HSP90 with NMS-E973 inhibitor bound==
 <StructureSection load='4b7p' size='340' side='right' caption='[[4b7p]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4b7p]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4B7P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4B7P FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4b7p]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4B7P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4B7P FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9UN:5-[2,4-DIHYDROXY-6-(4-NITROPHENOXY)PHENYL]-N-(1-METHYLPIPERIDIN-4-YL)-1,2-OXAZOLE-3-CARBOXAMIDE'>9UN</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1byq|1byq]], [[1osf|1osf]], [[1uy6|1uy6]], [[1uy7|1uy7]], [[1uy8|1uy8]], [[1uy9|1uy9]], [[1uyc|1uyc]], [[1uyd|1uyd]], [[1uye|1uye]], [[1uyf|1uyf]], [[1uyg|1uyg]], [[1uyh|1uyh]], [[1uyi|1uyi]], [[1uyk|1uyk]], [[1uyl|1uyl]], [[1yc1|1yc1]], [[1yc3|1yc3]], [[1yc4|1yc4]], [[1yer|1yer]], [[1yes|1yes]], [[1yet|1yet]], [[2bsm|2bsm]], [[2bt0|2bt0]], [[2bug|2bug]], [[2byh|2byh]], [[2byi|2byi]], [[2bz5|2bz5]], [[2c2l|2c2l]], [[2ccs|2ccs]], [[2cct|2cct]], [[2ccu|2ccu]], [[2fwy|2fwy]], [[2fwz|2fwz]], [[2jjc|2jjc]], [[2uwd|2uwd]], [[2vci|2vci]], [[2vcj|2vcj]], [[2wi1|2wi1]], [[2wi2|2wi2]], [[2wi3|2wi3]], [[2wi4|2wi4]], [[2wi5|2wi5]], [[2wi6|2wi6]], [[2wi7|2wi7]], [[2xab|2xab]], [[2xdk|2xdk]], [[2xdl|2xdl]], [[2xds|2xds]], [[2xdu|2xdu]], [[2xdx|2xdx]], [[2xhr|2xhr]], [[2xht|2xht]], [[2xhx|2xhx]], [[2xjg|2xjg]], [[2xjj|2xjj]], [[2xjx|2xjx]], [[2xk2|2xk2]], [[2ye2|2ye2]], [[2ye3|2ye3]], [[2ye4|2ye4]], [[2ye5|2ye5]], [[2ye6|2ye6]], [[2ye7|2ye7]], [[2ye8|2ye8]], [[2ye9|2ye9]], [[2yea|2yea]], [[2yeb|2yeb]], [[2yec|2yec]], [[2yed|2yed]], [[2yee|2yee]], [[2yef|2yef]], [[2yeg|2yeg]], [[2yeh|2yeh]], [[2yei|2yei]], [[2yej|2yej]], [[2yi0|2yi0]], [[2yi5|2yi5]], [[2yi6|2yi6]], [[2yi7|2yi7]], [[2yjw|2yjw]], [[2yjx|2yjx]], [[2yk2|2yk2]], [[2yk9|2yk9]], [[2ykb|2ykb]], [[2ykc|2ykc]], [[2yke|2yke]], [[2yki|2yki]], [[2ykj|2ykj]], [[4aif|4aif]], [[4awo|4awo]], [[4awp|4awp]], [[4awq|4awq]]</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4b7p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b7p OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4b7p RCSB], [http://www.ebi.ac.uk/pdbsum/4b7p PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4b7p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b7p OCA], [http://pdbe.org/4b7p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4b7p RCSB], [http://www.ebi.ac.uk/pdbsum/4b7p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4b7p ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 17: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4b7p" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 24: / Line 26: @@
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Ballinari, D]]
 [[Category: Brasca, M G]]

4b7p

From Proteopedia

Revision as of 00:24, 5 August 2016

Structure of HSP90 with NMS-E973 inhibitor bound

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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