5ggz

From Proteopedia

(Difference between revisions)

Revision as of 16:44, 9 March 2017

Crystal structure of novel inhibitor bound with Hsp90

Structural highlights

5ggz is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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 potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.

Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90.,Jiang F, Wang HJ, Jin YH, Zhang Q, Wang ZH, Jia JM, Liu F, Wang L, Bao QC, Li DD, You QD, Xu XL J Med Chem. 2016 Dec 8;59(23):10498-10519. Epub 2016 Nov 22. PMID:27933959^[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
↑ Jiang F, Wang HJ, Jin YH, Zhang Q, Wang ZH, Jia JM, Liu F, Wang L, Bao QC, Li DD, You QD, Xu XL. Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90. J Med Chem. 2016 Dec 8;59(23):10498-10519. Epub 2016 Nov 22. PMID:27933959 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b00912

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5ggz"

Categories: Chen, T T | Li, J | Xu, Y C | Chaperone-chaperone inhibitor complex | Hsp90

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 5ggz is ON HOLD
+==Crystal structure of novel inhibitor bound with Hsp90==
+<StructureSection load='5ggz' size='340' side='right' caption='[[5ggz]], [[Resolution|resolution]] 2.02&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5ggz]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5GGZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5GGZ FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6TN:[2,4-BIS(OXIDANYL)-5-PROPAN-2-YL-PHENYL]-(2-ETHOXY-7,8-DIHYDRO-5~{H}-PYRIDO[4,3-D]PYRIMIDIN-6-YL)METHANONE'>6TN</scene></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=5ggz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ggz OCA], [http://pdbe.org/5ggz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ggz RCSB], [http://www.ebi.ac.uk/pdbsum/5ggz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ggz ProSAT]</span></td></tr>
+</table>
+== Function ==
+[[http://www.uniprot.org/uniprot/HS90A_HUMAN 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.<ref>PMID:15937123</ref> <ref>PMID:11274138</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.
-Authors: Chen, T.T., Li, J., Xu, Y.C.
+Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90.,Jiang F, Wang HJ, Jin YH, Zhang Q, Wang ZH, Jia JM, Liu F, Wang L, Bao QC, Li DD, You QD, Xu XL J Med Chem. 2016 Dec 8;59(23):10498-10519. Epub 2016 Nov 22. PMID:27933959<ref>PMID:27933959</ref>
-Description: Crystal structure of novel inhibitor bound with Hsp90
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 5ggz" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Chen, T T]]
 [[Category: Li, J]]
-[[Category: Xu, Y.C]]
+[[Category: Xu, Y C]]
-[[Category: Chen, T.T]]
+[[Category: Chaperone-chaperone inhibitor complex]]
+[[Category: Hsp90]]

5ggz

From Proteopedia

Revision as of 16:44, 9 March 2017

Crystal structure of novel inhibitor bound with Hsp90

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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