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2qfo

From Proteopedia

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Current revision

HSP90 complexed with A143571 and A516383

Structural highlights

2qfo 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.
Method:	X-ray diffraction, Resolution 1.68Å
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]

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

The molecular chaperone HSP90 has been shown to facilitate cancer cell survival by stabilizing key proteins responsible for a malignant phenotype. We report here the results of parallel fragment-based drug design approaches in the design of novel HSP90 inhibitors. Initial aminopyrimidine leads were elaborated using high-throughput organic synthesis to yield nanomolar inhibitors of the enzyme. Second site leads were also identified which bound to HSP90 in two distinct conformations, an 'open' and 'closed' form. Intriguingly, linked fragment approaches targeting both of these conformations were successful in producing novel, micromolar inhibitors. Overall, this study shows that, with only a few fragment hits, multiple lead series can be generated for HSP90 due to the inherent flexibility of the active site. Thus, ample opportunities exist to use these lead series in the development of clinically useful HSP90 inhibitors for the treatment of cancers.

Discovery and design of novel HSP90 inhibitors using multiple fragment-based design strategies.,Huth JR, Park C, Petros AM, Kunzer AR, Wendt MD, Wang X, Lynch CL, Mack JC, Swift KM, Judge RA, Chen J, Richardson PL, Jin S, Tahir SK, Matayoshi ED, Dorwin SA, Ladror US, Severin JM, Walter KA, Bartley DM, Fesik SW, Elmore SW, Hajduk PJ Chem Biol Drug Des. 2007 Jul;70(1):1-12. PMID:17630989^[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
↑ Huth JR, Park C, Petros AM, Kunzer AR, Wendt MD, Wang X, Lynch CL, Mack JC, Swift KM, Judge RA, Chen J, Richardson PL, Jin S, Tahir SK, Matayoshi ED, Dorwin SA, Ladror US, Severin JM, Walter KA, Bartley DM, Fesik SW, Elmore SW, Hajduk PJ. Discovery and design of novel HSP90 inhibitors using multiple fragment-based design strategies. Chem Biol Drug Des. 2007 Jul;70(1):1-12. PMID:17630989 doi:10.1111/j.1747-0285.2007.00535.x

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/2qfo"

Categories: Homo sapiens | Large Structures | Park CH

@@ Line 1: / Line 1: @@
 ==HSP90 complexed with A143571 and A516383==
-<StructureSection load='2qfo' size='340' side='right' caption='[[2qfo]], [[Resolution|resolution]] 1.68&Aring;' scene=''>
+<StructureSection load='2qfo' size='340' side='right'caption='[[2qfo]], [[Resolution|resolution]] 1.68&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2qfo]] is a 2 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=2QFO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2QFO FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2qfo]] is a 2 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=2QFO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2QFO FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=A13:4-METHYL-6-(TRIFLUOROMETHYL)PYRIMIDIN-2-AMINE'>A13</scene>, <scene name='pdbligand=A51:(3E)-3-[(PHENYLAMINO)METHYLIDENE]DIHYDROFURAN-2(3H)-ONE'>A51</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]] 1.68&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HSP90AA1, HSP90A, HSPC1, HSPCA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A13:4-METHYL-6-(TRIFLUOROMETHYL)PYRIMIDIN-2-AMINE'>A13</scene>, <scene name='pdbligand=A51:(3E)-3-[(PHENYLAMINO)METHYLIDENE]DIHYDROFURAN-2(3H)-ONE'>A51</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=2qfo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qfo OCA], [http://pdbe.org/2qfo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2qfo RCSB], [http://www.ebi.ac.uk/pdbsum/2qfo PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2qfo ProSAT]</span></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=2qfo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qfo OCA], [https://pdbe.org/2qfo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2qfo RCSB], [https://www.ebi.ac.uk/pdbsum/2qfo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2qfo 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>
+[https://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 31: / Line 31: @@
 ==See Also==
-*[[Heat Shock Proteins|Heat Shock Proteins]]
+*[[Heat Shock Protein structures|Heat Shock Protein structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Park, C H]]
+[[Category: Large Structures]]
-[[Category: Atp-binding]]
+[[Category: Park CH]]
-[[Category: Chaperone]]
-[[Category: Nucleotide-binding]]
-[[Category: Phosphoprotein]]
-[[Category: Protein-inhibitor complex]]
-[[Category: Stress response]]

2qfo

From Proteopedia

Current revision

HSP90 complexed with A143571 and A516383

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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