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| | <StructureSection load='2xx4' size='340' side='right'caption='[[2xx4]], [[Resolution|resolution]] 2.20Å' scene=''> | | <StructureSection load='2xx4' size='340' side='right'caption='[[2xx4]], [[Resolution|resolution]] 2.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2xx4]] 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=2XX4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2XX4 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2xx4]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2XX4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2XX4 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=13I:(E)-ETHYL+13-CHLORO-14,16-DIHYDROXY-1,11-DIOXO-1,2,3,4,7,8,9,10,11,12-DECAHYDROBENZO[C][1]AZACYCLOTETRADECINE-10-CARBOXYLATE'>13I</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]] 2.199Å</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]], [[2xx5|2xx5]], [[2bre|2bre]], [[2iws|2iws]], [[2wer|2wer]], [[2brc|2brc]], [[1zwh|1zwh]], [[1usu|1usu]], [[1ah8|1ah8]], [[2vw5|2vw5]], [[2cgf|2cgf]], [[2ygf|2ygf]], [[1am1|1am1]], [[2yge|2yge]], [[2iwx|2iwx]], [[2cge|2cge]], [[1zw9|1zw9]], [[2wep|2wep]], [[2akp|2akp]], [[1us7|1us7]], [[2vwc|2vwc]], [[2cg9|2cg9]], [[2xd6|2xd6]], [[2yga|2yga]], [[1ah6|1ah6]], [[1usv|1usv]], [[1bgq|1bgq]], [[1amw|1amw]], [[2weq|2weq]], [[2xx2|2xx2]], [[2iwu|2iwu]]</div></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=13I:(E)-ETHYL+13-CHLORO-14,16-DIHYDROXY-1,11-DIOXO-1,2,3,4,7,8,9,10,11,12-DECAHYDROBENZO[C][1]AZACYCLOTETRADECINE-10-CARBOXYLATE'>13I</scene></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=2xx4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xx4 OCA], [https://pdbe.org/2xx4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2xx4 RCSB], [https://www.ebi.ac.uk/pdbsum/2xx4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2xx4 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=2xx4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xx4 OCA], [https://pdbe.org/2xx4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2xx4 RCSB], [https://www.ebi.ac.uk/pdbsum/2xx4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2xx4 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[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>
| + | [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> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Atcc 18824]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Moody, C J]] | + | [[Category: Saccharomyces cerevisiae]] |
| - | [[Category: Pearl, L H]] | + | [[Category: Moody CJ]] |
| - | [[Category: Prodromou, C]] | + | [[Category: Pearl LH]] |
| - | [[Category: Roe, S M]] | + | [[Category: Prodromou C]] |
| - | [[Category: Chaperone]] | + | [[Category: Roe SM]] |
| Structural highlights
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]
Publication Abstract from PubMed
A series of resorcylic acid macrolactams, nitrogen analogues of the naturally occurring macrolactone radicicol, have 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, as key steps, ring opening of an isocoumarin intermediate, followed by a ring-closing metathesis reaction to form the macrocycle. Subsequent manipulation of the ester group into a range of amides allows access to a range of new macrolactams following deprotection of the two phenolic groups. These new resorcylic acid lactams exhibit metabolic stability greater than that of related lactone counterparts, while co-crystallization of three macrolactams with the N-terminal domain ATP site of Hsp90 confirms that they bind in a similar way to the natural product radicicol and to our previous synthetic lactone analogues. Interestingly, however, in the case of the N-benzylamide, additional binding to a hydrophobic pocket of the protein was observed. In biological assays, the new macrocyclic lactams exhibit a biological profile equivalent or superior to that of the related lactones and show the established molecular signature of Hsp90 inhibitors in human colon cancer cells.
Targeting the Hsp90 Molecular Chaperone with Novel Macrolactams. Synthesis, Structural, Binding, and Cellular Studies.,Day JE, Sharp SY, Rowlands MG, Aherne W, Hayes A, Raynaud FI, Lewis W, Roe SM, Prodromou C, Pearl LH, Workman P, Moody CJ ACS Chem Biol. 2011 Oct 4. PMID:21932796[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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, Hayes A, Raynaud FI, Lewis W, Roe SM, Prodromou C, Pearl LH, Workman P, Moody CJ. Targeting the Hsp90 Molecular Chaperone with Novel Macrolactams. Synthesis, Structural, Binding, and Cellular Studies. ACS Chem Biol. 2011 Oct 4. PMID:21932796 doi:10.1021/cb200196e
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