View source for 7pjn


==Crystal Structure of Ivosidenib-resistant IDH1 variant R132C S280F in complex with NADPH and inhibitor DS-1001B==
<StructureSection load='7pjn' size='340' side='right'caption='[[7pjn]], [[Resolution|resolution]] 2.45&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7pjn]] 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=7PJN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7PJN 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]] 2.45&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7SU:(~{E})-3-[1-[[5-(2-fluoranylpropan-2-yl)-3-[2,4,6-tris(chloranyl)phenyl]-1,2-oxazol-4-yl]carbonyl]-3-methyl-indol-4-yl]prop-2-enoic+acid'>7SU</scene>, <scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=CSD:3-SULFINOALANINE'>CSD</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</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=7pjn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7pjn OCA], [https://pdbe.org/7pjn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7pjn RCSB], [https://www.ebi.ac.uk/pdbsum/7pjn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7pjn 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 ==
Ivosidenib, an inhibitor of isocitrate dehydrogenase 1 (IDH1) R132C and R132H variants, is approved for the treatment of acute myeloid leukaemia (AML). Resistance to ivosidenib due to a second site mutation of IDH1 R132C, leading to IDH1 R132C/S280F, has emerged. We describe biochemical, crystallographic, and cellular studies on the IDH1 R132C/S280F and R132H/S280F variants that inform on the mechanism of second-site resistance, which involves both modulation of inhibitor binding at the IDH1 dimer-interface and alteration of kinetic properties, which enable more efficient 2-HG production relative to IDH1 R132C and IDH1 R132H. Importantly, the biochemical and cellular results demonstrate that it should be possible to overcome S280F mediated resistance in AML patients by using alternative inhibitors, including some presently in phase 2 clinical trials.

Resistance to the isocitrate dehydrogenase 1 mutant inhibitor ivosidenib can be overcome by alternative dimer-interface binding inhibitors.,Reinbold R, Hvinden IC, Rabe P, Herold RA, Finch A, Wood J, Morgan M, Staudt M, Clifton IJ, Armstrong FA, McCullagh JSO, Redmond J, Bardella C, Abboud MI, Schofield CJ Nat Commun. 2022 Aug 15;13(1):4785. doi: 10.1038/s41467-022-32436-4. PMID:35970853<ref>PMID:35970853</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7pjn" style="background-color:#fffaf0;"></div>

==See Also==
*[[Isocitrate dehydrogenase 3D structures|Isocitrate dehydrogenase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Abboud MI]]
[[Category: Clifton IJ]]
[[Category: Rabe P]]
[[Category: Reinbold R]]
[[Category: Schofield CJ]]