2xd6

From Proteopedia

(Difference between revisions)

Revision as of 08:38, 10 November 2021

Hsp90 complexed with a resorcylic acid macrolactone.

Structural highlights

2xd6 is a 1 chain structure with sequence from Atcc 18824. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	1hk7, 1a4h, 1us7, 2bre, 2vwc, 2cg9, 1ah6, 1bgq, 1usv, 2iws, 2wer, 1amw, 1usu, 2brc, 1zwh, 1ah8, 2weq, 2vw5, 2cgf, 2iwu, 1am1, 2vls, 2iwx, 2cge, 2akp, 1zw9, 2wep
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[HSP82_YEAST] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. The nucleotide-free form of the dimer is found in an open conformation in which the N-termini are not dimerized and the complex is ready for client protein binding. Binding of ATP induces large conformational changes, resulting in the formation of a ring-like closed structure in which the N-terminal domains associate intramolecularly with the middle domain and also dimerize with each other, stimulating their intrinsic ATPase activity and acting as a clamp on the substrate. Finally, ATP hydrolysis results in the release of the substrate. 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. Required for growth at high temperatures.^[1]

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

A series of resorcylic acid macrolactones, analogues of the natural product radicicol has been prepared by chemical synthesis, and evaluated as inhibitors of heat shock protein 90 (Hsp90), an emerging attractive target for novel cancer therapeutic agents. The synthesis involves acylation of an ortho-toluic acid dianion, esterification, followed by a ring-closing metathesis to form the macrocycle. Subsequent manipulation of the protected hydroxymethyl side chain allows access to a range of new analogues following deprotection of the two phenolic groups. Co-crystallization of one of the new macrolactones with the N-terminal domain of yeast Hsp90 confirms that it binds in a similar way to the natural product radicicol and to our previous synthetic analogues, but that the introduction of the additional hydroxymethyl substituent appears to result in an unexpected change in conformation of the macrocyclic ring. As a result of this conformational change, the compounds bound less favorably to Hsp90.

Inhibition of Hsp90 with Resorcylic Acid Macrolactones: Synthesis and Binding Studies.,Day JE, Sharp SY, Rowlands MG, Aherne W, Lewis W, Roe SM, Prodromou C, Pearl LH, Workman P, Moody CJ Chemistry. 2010 Jul 26. PMID:20661961^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Proisy N, Sharp SY, Boxall K, Connelly S, Roe SM, Prodromou C, Slawin AM, Pearl LH, Workman P, Moody CJ. Inhibition of Hsp90 with synthetic macrolactones: synthesis and structural and biological evaluation of ring and conformational analogs of radicicol. Chem Biol. 2006 Nov;13(11):1203-15. PMID:17114002 doi:10.1016/j.chembiol.2006.09.015
↑ Day JE, Sharp SY, Rowlands MG, Aherne W, Lewis W, Roe SM, Prodromou C, Pearl LH, Workman P, Moody CJ. Inhibition of Hsp90 with Resorcylic Acid Macrolactones: Synthesis and Binding Studies. Chemistry. 2010 Jul 26. PMID:20661961 doi:10.1002/chem.201001119

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/2xd6"

@@ Line 3: / Line 3: @@
 <StructureSection load='2xd6' size='340' side='right'caption='[[2xd6]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2xd6]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Atcc_18824 Atcc 18824]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2XD6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2XD6 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2xd6]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Atcc_18824 Atcc 18824]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2XD6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2XD6 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=XD6:(5Z)-13-CHLORO-14,16-DIHYDROXY-1,11-DIOXO-3,4,7,8,9,10,11,12-OCTAHYDRO-1H-2-BENZOXACYCLOTETRADECINE-6-CARBALDEHYDE'>XD6</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=XD6:(5Z)-13-CHLORO-14,16-DIHYDROXY-1,11-DIOXO-3,4,7,8,9,10,11,12-OCTAHYDRO-1H-2-BENZOXACYCLOTETRADECINE-6-CARBALDEHYDE'>XD6</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1hk7|1hk7]], [[1a4h|1a4h]], [[1us7|1us7]], [[2bre|2bre]], [[2vwc|2vwc]], [[2cg9|2cg9]], [[1ah6|1ah6]], [[1bgq|1bgq]], [[1usv|1usv]], [[2iws|2iws]], [[2wer|2wer]], [[1amw|1amw]], [[1usu|1usu]], [[2brc|2brc]], [[1zwh|1zwh]], [[1ah8|1ah8]], [[2weq|2weq]], [[2vw5|2vw5]], [[2cgf|2cgf]], [[2iwu|2iwu]], [[1am1|1am1]], [[2vls|2vls]], [[2iwx|2iwx]], [[2cge|2cge]], [[2akp|2akp]], [[1zw9|1zw9]], [[2wep|2wep]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1hk7|1hk7]], [[1a4h|1a4h]], [[1us7|1us7]], [[2bre|2bre]], [[2vwc|2vwc]], [[2cg9|2cg9]], [[1ah6|1ah6]], [[1bgq|1bgq]], [[1usv|1usv]], [[2iws|2iws]], [[2wer|2wer]], [[1amw|1amw]], [[1usu|1usu]], [[2brc|2brc]], [[1zwh|1zwh]], [[1ah8|1ah8]], [[2weq|2weq]], [[2vw5|2vw5]], [[2cgf|2cgf]], [[2iwu|2iwu]], [[1am1|1am1]], [[2vls|2vls]], [[2iwx|2iwx]], [[2cge|2cge]], [[2akp|2akp]], [[1zw9|1zw9]], [[2wep|2wep]]</div></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=2xd6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xd6 OCA], [http://pdbe.org/2xd6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2xd6 RCSB], [http://www.ebi.ac.uk/pdbsum/2xd6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2xd6 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=2xd6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xd6 OCA], [https://pdbe.org/2xd6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2xd6 RCSB], [https://www.ebi.ac.uk/pdbsum/2xd6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2xd6 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/HSP82_YEAST HSP82_YEAST]] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. The nucleotide-free form of the dimer is found in an open conformation in which the N-termini are not dimerized and the complex is ready for client protein binding. Binding of ATP induces large conformational changes, resulting in the formation of a ring-like closed structure in which the N-terminal domains associate intramolecularly with the middle domain and also dimerize with each other, stimulating their intrinsic ATPase activity and acting as a clamp on the substrate. Finally, ATP hydrolysis results in the release of the substrate. 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. Required for growth at high temperatures.<ref>PMID:17114002</ref>
+[[https://www.uniprot.org/uniprot/HSP82_YEAST HSP82_YEAST]] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. The nucleotide-free form of the dimer is found in an open conformation in which the N-termini are not dimerized and the complex is ready for client protein binding. Binding of ATP induces large conformational changes, resulting in the formation of a ring-like closed structure in which the N-terminal domains associate intramolecularly with the middle domain and also dimerize with each other, stimulating their intrinsic ATPase activity and acting as a clamp on the substrate. Finally, ATP hydrolysis results in the release of the substrate. 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. Required for growth at high temperatures.<ref>PMID:17114002</ref>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]

2xd6

From Proteopedia

Revision as of 08:38, 10 November 2021

Hsp90 complexed with a resorcylic acid macrolactone.

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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