OCA at 10:55, 22 May 2024

OCA — Wed, 22 May 2024 10:55:37 GMT

←Older revision		Revision as of 10:55, 22 May 2024
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-	'''Unreleased structure'''

-	~~The entry~~ 8vhd is ~~ON HOLD~~	+	==Crystal Structure of Human IDH1 R132Q in complex with NADPH and Isocitrate==
		+	<StructureSection load='8vhd' size='340' side='right'caption='[[8vhd]], [[Resolution\|resolution]] 2.38Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8vhd]] is a 4 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=8VHD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8VHD FirstGlance]. <br>
		+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.38Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ICT:ISOCITRIC+ACID'>ICT</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</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=8vhd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8vhd OCA], [https://pdbe.org/8vhd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8vhd RCSB], [https://www.ebi.ac.uk/pdbsum/8vhd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8vhd ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[https://www.uniprot.org/uniprot/IDHC_HUMAN IDHC_HUMAN] Defects in IDH1 are involved in the development of glioma (GLM) [MIM:[https://omim.org/entry/137800 137800]. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Note=Mutations affecting Arg-132 are tissue-specific, and suggest that this residue plays a unique role in the development of high-grade gliomas. Mutations of Arg-132 to Cys, His, Leu or Ser abolish magnesium binding and abolish the conversion of isocitrate to alpha-ketoglutarate. Instead, alpha-ketoglutarate is converted to R(-)-2-hydroxyglutarate. Elevated levels of R(-)-2-hydroxyglutarate are correlated with an elevated risk of malignant brain tumors.
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/IDHC_HUMAN IDHC_HUMAN]
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Mutations in human isocitrate dehydrogenase 1 (IDH1) drive tumor formation in a variety of cancers by replacing its conventional activity with a neomorphic activity that generates an oncometabolite. Little is understood of the mechanistic differences among tumor-driving IDH1 mutants. We previously reported that the R132Q mutant unusually preserves conventional activity while catalyzing robust oncometabolite production, allowing an opportunity to compare these reaction mechanisms within a single active site. Here, we employ static and dynamic structural methods and observe that, compared to R132H, the R132Q active site adopts a conformation primed for catalysis with optimized substrate binding and hydride transfer to drive improved conventional and neomorphic activity over R132H. This active site remodeling reveals a possible mechanism of resistance to selective mutant IDH1 therapeutic inhibitors. This work enhances our understanding of fundamental IDH1 mechanisms while pinpointing regions for improving inhibitor selectivity.

-	~~Authors: Mealka~~, M., ~~Sohl~~, C.D., ~~Huxford~~, T.	+	Active site remodeling in tumor-relevant IDH1 mutants drives distinct kinetic features and potential resistance mechanisms.,Mealka M, Sierra NA, Avellaneda Matteo D, Albekioni E, Khoury R, Mai T, Conley BM, Coleman NJ, Sabo KA, Komives EA, Bobkov AA, Cooksy AL, Silletti S, Schiffer JM, Huxford T, Sohl CD Nat Commun. 2024 May 6;15(1):3785. doi: 10.1038/s41467-024-48277-2. PMID:38710674<ref>PMID:38710674</ref>

-	~~Description: Crystal Structure~~ of ~~Human IDH1 R132Q in complex with NADPH and Isocitrate~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
-	[[Category: ~~Sohl, C.D~~]]	+	<div class="pdbe-citations 8vhd" style="background-color:#fffaf0;"></div>
-	[[Category: Huxford, T]]	+	== References ==
-	[[Category: Mealka, M]]	+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Homo sapiens]]
		+	[[Category: Large Structures]]
		+	[[Category: Huxford T]]
		+	[[Category: Mealka M]]
		+	[[Category: Sohl CD]]

OCA: Protected "8vhd" [edit=sysop:move=sysop]

OCA — Wed, 10 Jan 2024 09:23:36 GMT

Protected "8vhd" [edit=sysop:move=sysop]

←Older revision

Revision as of 09:23, 10 January 2024

OCA: New page: '''Unreleased structure''' The entry 8vhd is ON HOLD Authors: Mealka, M., Sohl, C.D., Huxford, T. Description: Crystal Structure of Human IDH1 R132Q in complex with NADPH and Isocitrat...

OCA — Wed, 10 Jan 2024 09:23:35 GMT

New page: '''Unreleased structure''' The entry 8vhd is ON HOLD Authors: Mealka, M., Sohl, C.D., Huxford, T. Description: Crystal Structure of Human IDH1 R132Q in complex with NADPH and Isocitrat...

New page

'''Unreleased structure'''

The entry 8vhd is ON HOLD

Authors: Mealka, M., Sohl, C.D., Huxford, T.

Description: Crystal Structure of Human IDH1 R132Q in complex with NADPH and Isocitrate
[[Category: Unreleased Structures]]
[[Category: Sohl, C.D]]
[[Category: Huxford, T]]
[[Category: Mealka, M]]

8vhd - Revision history

OCA at 10:55, 22 May 2024

OCA: Protected "8vhd" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 8vhd is ON HOLD Authors: Mealka, M., Sohl, C.D., Huxford, T. Description: Crystal Structure of Human IDH1 R132Q in complex with NADPH and Isocitrat...