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3hek

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Revision as of 00:59, 25 December 2014

HSP90 N-terminal domain in complex with 1-{4-[(2R)-1-(5-chloro-2,4-dihydroxybenzoyl)pyrrolidin-2-yl]benzyl}-3,3-difluoropyrrolidinium

Structural highlights

3hek is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Gene:	HSP90, HSP90A, HSP90AA1, HSPC1, HSPCA (Homo sapiens)
Resources:	FirstGlance, OCA, RCSB, PDBsum

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]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

As part of an oncology chemistry program directed toward discovery of orally bioavailable inhibitors of the 90 kDa heat shock protein (Hsp90), several solution-phase libraries were designed and prepared. A 2 x 89 library of racemic resorcinol amides was prepared affording 131 purified compounds. After evaluation in a binding assay, followed by an AKT-Luminex cellular assay, three potent analogs had functional activity between 0.1 and 0.3 microM. Resolution by preparative chiral SFC chromatography led to (+)-15, (+)-16, and (+)-17 having functional IC(50) = 27, 43, and 190 nM, respectively. (+)-15 exhibited high clearance in human hepatocytes driven primarily by glucuronidation as confirmed by metabolite identification. A second 8 x 14 exploratory library was designed to investigate heterocyclic replacements of the resorcinol ring. The second library highlights the use of the (-)-sparteine-mediated enantioselective Pd-catalyzed alpha-arylation of N-Boc-pyrrolidine to prepare chiral 2-arylpyrrolidines in parallel.

Solution-phase parallel synthesis of Hsp90 inhibitors.,Cho-Schultz S, Patten MJ, Huang B, Elleraas J, Gajiwala KS, Hickey MJ, Wang J, Mehta PP, Kang P, Gehring MR, Kung PP, Sutton SC J Comb Chem. 2009 Sep-Oct;11(5):860-74. PMID:19583220^[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
↑ Cho-Schultz S, Patten MJ, Huang B, Elleraas J, Gajiwala KS, Hickey MJ, Wang J, Mehta PP, Kang P, Gehring MR, Kung PP, Sutton SC. Solution-phase parallel synthesis of Hsp90 inhibitors. J Comb Chem. 2009 Sep-Oct;11(5):860-74. PMID:19583220 doi:10.1021/cc900056d

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3hek"

@@ Line 3: / Line 3: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[3hek]] is a 2 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=3HEK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3HEK FirstGlance]. <br>
-</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BD0:(1S,2R)-1-[(5-CHLORO-2,4-DIHYDROXYPHENYL)CARBONYL]-2-{4-[(3,3-DIFLUOROPYRROLIDIN-1-YL)METHYL]PHENYL}PYRROLIDINIUM'>BD0</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene><br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BD0:(1S,2R)-1-[(5-CHLORO-2,4-DIHYDROXYPHENYL)CARBONYL]-2-{4-[(3,3-DIFLUOROPYRROLIDIN-1-YL)METHYL]PHENYL}PYRROLIDINIUM'>BD0</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
-<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HSP90, HSP90A, HSP90AA1, HSPC1, HSPCA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HSP90, HSP90A, HSP90AA1, HSPC1, HSPCA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
-<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3hek FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3hek OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3hek RCSB], [http://www.ebi.ac.uk/pdbsum/3hek 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=3hek FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3hek OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3hek RCSB], [http://www.ebi.ac.uk/pdbsum/3hek PDBsum]</span></td></tr>
-<table>
+</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>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 33: / Line 35: @@
 </StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Gajiwala, K S.]]
+[[Category: Gajiwala, K S]]
 [[Category: Atp-binding]]
 [[Category: Chaperone]]

3hek

From Proteopedia

Revision as of 00:59, 25 December 2014

HSP90 N-terminal domain in complex with 1-{4-[(2R)-1-(5-chloro-2,4-dihydroxybenzoyl)pyrrolidin-2-yl]benzyl}-3,3-difluoropyrrolidinium

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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