3nmq

From Proteopedia

(Difference between revisions)

Revision as of 09:17, 6 September 2023

Hsp90b N-terminal domain in complex with EC44, a pyrrolo-pyrimidine methoxypyridine inhibitor

Structural highlights

3nmq is a 1 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 2.2Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

HS90B_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 molecular chaperone involved in folding and stabilizing multiple intracellular proteins that have roles in cell activation and proliferation. Many Hsp90 client proteins in tumor cells are mutated or overexpressed oncogenic proteins driving cancer cell growth, leading to the acceptance of Hsp90 as a potential therapeutic target for cancer. Because several signal transduction molecules that are dependent on Hsp90 function are also involved in activation of innate and adaptive cells of the immune system, we investigated the mechanism by which inhibiting Hsp90 leads to therapeutic efficacy in rodent models of inflammation and autoimmunity. EC144, a synthetic Hsp90 inhibitor, blocked LPS-induced TLR4 signaling in RAW 264.7 cells by inhibiting activation of ERK1/2, MEK1/2, JNK, and p38 MAPK but not NF-kappaB. Ex vivo LPS-stimulated CD11b(+) peritoneal exudate cells from EC144-treated mice were blocked from phosphorylating tumor progression locus 2, MEK1/2, and ERK1/2. Consequently, EC144-treated mice were resistant to LPS administration and had suppressed systemic TNF-alpha release. Inhibiting Hsp90 also blocked in vitro CD4(+) T cell proliferation in mouse and human MLRs. In vivo, semitherapeutic administration of EC144 blocked disease development in rat collagen-induced arthritis by suppressing the inflammatory response. In a mouse collagen-induced arthritis model, EC144 also suppressed disease development, which correlated with a suppressed Ag-specific Ab response and a block in activation of Ag-specific CD4(+) T cells. Our results describe mechanisms by which blocking Hsp90 function may be applicable to treatment of autoimmune diseases involving inflammation and activation of the adaptive immune response.

EC144, a Synthetic Inhibitor of Heat Shock Protein 90, Blocks Innate and Adaptive Immune Responses in Models of Inflammation and Autoimmunity.,Yun TJ, Harning EK, Giza K, Rabah D, Li P, Arndt JW, Luchetti D, Biamonte MA, Shi J, Lundgren K, Manning A, Kehry MR J Immunol. 2011 Jan 1;186(1):563-75. Epub 2010 Dec 3. PMID:21131419^[3]

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

References

↑ Chadli A, Graham JD, Abel MG, Jackson TA, Gordon DF, Wood WM, Felts SJ, Horwitz KB, Toft D. GCUNC-45 is a novel regulator for the progesterone receptor/hsp90 chaperoning pathway. Mol Cell Biol. 2006 Mar;26(5):1722-30. PMID:16478993 doi:http://dx.doi.org/26/5/1722
↑ Retzlaff M, Stahl M, Eberl HC, Lagleder S, Beck J, Kessler H, Buchner J. Hsp90 is regulated by a switch point in the C-terminal domain. EMBO Rep. 2009 Oct;10(10):1147-53. Epub 2009 Aug 21. PMID:19696785 doi:http://dx.doi.org/embor2009153
↑ Yun TJ, Harning EK, Giza K, Rabah D, Li P, Arndt JW, Luchetti D, Biamonte MA, Shi J, Lundgren K, Manning A, Kehry MR. EC144, a Synthetic Inhibitor of Heat Shock Protein 90, Blocks Innate and Adaptive Immune Responses in Models of Inflammation and Autoimmunity. J Immunol. 2011 Jan 1;186(1):563-75. Epub 2010 Dec 3. PMID:21131419 doi:10.4049/jimmunol.1000222

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

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

@@ Line 3: / Line 3: @@
 <StructureSection load='3nmq' size='340' side='right'caption='[[3nmq]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3nmq]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3NMQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3NMQ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3nmq]] is a 1 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=3NMQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3NMQ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7PP:5-{2-AMINO-4-CHLORO-7-[(4-METHOXY-3,5-DIMETHYLPYRIDIN-2-YL)METHYL]-7H-PYRROLO[2,3-D]PYRIMIDIN-5-YL}-2-METHYLPENT-4-YN-2-OL'>7PP</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]] 2.2&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HSP90AB1, HSP90B, HSPC2, HSPCB ([https://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=7PP:5-{2-AMINO-4-CHLORO-7-[(4-METHOXY-3,5-DIMETHYLPYRIDIN-2-YL)METHYL]-7H-PYRROLO[2,3-D]PYRIMIDIN-5-YL}-2-METHYLPENT-4-YN-2-OL'>7PP</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=3nmq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nmq OCA], [https://pdbe.org/3nmq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3nmq RCSB], [https://www.ebi.ac.uk/pdbsum/3nmq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3nmq ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/HS90B_HUMAN HS90B_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:16478993</ref> <ref>PMID:19696785</ref>
+[https://www.uniprot.org/uniprot/HS90B_HUMAN HS90B_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:16478993</ref> <ref>PMID:19696785</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 26: / Line 26: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Arndt, J W]]
+[[Category: Arndt JW]]
-[[Category: Giza, K]]
+[[Category: Giza K]]
-[[Category: Harning, E K]]
+[[Category: Harning EK]]
-[[Category: Kehry, M R]]
+[[Category: Kehry MR]]
-[[Category: Li, P]]
+[[Category: Li P]]
-[[Category: Luchetti, D]]
+[[Category: Luchetti D]]
-[[Category: Manning, A]]
+[[Category: Manning A]]
-[[Category: Rabah, D]]
+[[Category: Rabah D]]
-[[Category: Shi, J]]
+[[Category: Shi J]]
-[[Category: Yun, T J]]
+[[Category: Yun TJ]]
-[[Category: Atpase]]
-[[Category: Chaperone-chaperone inhibitor complex]]

3nmq

From Proteopedia

Revision as of 09:17, 6 September 2023

Hsp90b N-terminal domain in complex with EC44, a pyrrolo-pyrimidine methoxypyridine inhibitor

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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