5i96

From Proteopedia

(Difference between revisions)

Current revision

Crystal Structure of Human Mitochondrial Isocitrate Dehydrogenase (IDH2) R140Q Mutant Homodimer in Complex with AG-221 (Enasidenib) Inhibitor.

Structural highlights

5i96 is a 2 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 1.55Å
Ligands:	, , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

IDHP_HUMAN D-2-hydroxyglutaric aciduria. Defects in IDH2 are the cause of D-2-hydroxyglutaric aciduria type 2 (D2HGA2) [MIM:613657. D2HGA2 is a neurometabolic disorder causing developmental delay, epilepsy, hypotonia, and dysmorphic features. Both a mild and a severe phenotype exist. The severe phenotype is homogeneous and is characterized by early infantile-onset epileptic encephalopathy and cardiomyopathy. The mild phenotype has a more variable clinical presentation. Diagnosis is based on the presence of an excess of D-2-hydroxyglutaric acid in the urine.^[1]

Function

IDHP_HUMAN Plays a role in intermediary metabolism and energy production. It may tightly associate or interact with the pyruvate dehydrogenase complex.

Publication Abstract from PubMed

Somatic gain-of-function mutations in isocitrate dehydrogenase (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite, (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits alpha-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the Tet family, causing epigenetic dysregulation and a block in cellular differentiation. In vitro studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG production and induced cellular differentiation in primary human IDH2 mutation-positive acute myeloid leukemia (AML) cells ex vivo and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2R140Q-mutant AML xenograft mouse model. These findings supported initiation of the ongoing clinical trials of AG-221 in patients with IDH2 mutation-positive advanced hematologic malignancies.

AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations.,Yen K, Travins J, Wang F, David MD, Artin E, Straley K, Padyana A, Gross S, DeLaBarre B, Tobin E, Chen Y, Nagaraja R, Choe S, Jin L, Konteatis Z, Cianchetta G, Saunders JO, Salituro FG, Quivoron C, Opolon P, Bawa O, Saada V, Paci A, Broutin S, Bernard OA, de Botton S, Marteyn BS, Pilichowska M, Xu Y, Fang C, Jiang F, Wei W, Jin S, Silverman L, Liu W, Yang H, Dang L, Dorsch M, Penard-Lacronique V, Biller SA, Su SM Cancer Discov. 2017 Feb 13. pii: CD-16-1034. doi: 10.1158/2159-8290.CD-16-1034. PMID:28193778^[2]

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

References

↑ Kranendijk M, Struys EA, van Schaftingen E, Gibson KM, Kanhai WA, van der Knaap MS, Amiel J, Buist NR, Das AM, de Klerk JB, Feigenbaum AS, Grange DK, Hofstede FC, Holme E, Kirk EP, Korman SH, Morava E, Morris A, Smeitink J, Sukhai RN, Vallance H, Jakobs C, Salomons GS. IDH2 mutations in patients with D-2-hydroxyglutaric aciduria. Science. 2010 Oct 15;330(6002):336. doi: 10.1126/science.1192632. Epub 2010 Sep, 16. PMID:20847235 doi:http://dx.doi.org/10.1126/science.1192632
↑ Yen K, Travins J, Wang F, David MD, Artin E, Straley K, Padyana A, Gross S, DeLaBarre B, Tobin E, Chen Y, Nagaraja R, Choe S, Jin L, Konteatis Z, Cianchetta G, Saunders JO, Salituro FG, Quivoron C, Opolon P, Bawa O, Saada V, Paci A, Broutin S, Bernard OA, de Botton S, Marteyn BS, Pilichowska M, Xu Y, Fang C, Jiang F, Wei W, Jin S, Silverman L, Liu W, Yang H, Dang L, Dorsch M, Penard-Lacronique V, Biller SA, Su SM. AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations. Cancer Discov. 2017 Feb 13. pii: CD-16-1034. doi: 10.1158/2159-8290.CD-16-1034. PMID:28193778 doi:http://dx.doi.org/10.1158/2159-8290.CD-16-1034

1 Structural highlights
2 Disease
3 Function
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/5i96"

@@ Line 3: / Line 3: @@
 <StructureSection load='5i96' size='340' side='right'caption='[[5i96]], [[Resolution|resolution]] 1.55&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5i96]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5I96 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5I96 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5i96]] is a 2 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=5I96 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5I96 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=69Q:2-METHYL-1-[(4-[6-(TRIFLUOROMETHYL)PYRIDIN-2-YL]-6-{[2-(TRIFLUOROMETHYL)PYRIDIN-4-YL]AMINO}-1,3,5-TRIAZIN-2-YL)AMINO]PROPAN-2-OL'>69Q</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</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]] 1.55&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5i95|5i95]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=69Q:2-METHYL-1-[(4-[6-(TRIFLUOROMETHYL)PYRIDIN-2-YL]-6-{[2-(TRIFLUOROMETHYL)PYRIDIN-4-YL]AMINO}-1,3,5-TRIAZIN-2-YL)AMINO]PROPAN-2-OL'>69Q</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Isocitrate_dehydrogenase_(NADP(+)) Isocitrate dehydrogenase (NADP(+))], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.42 1.1.1.42] </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=5i96 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5i96 OCA], [https://pdbe.org/5i96 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5i96 RCSB], [https://www.ebi.ac.uk/pdbsum/5i96 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5i96 ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5i96 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5i96 OCA], [http://pdbe.org/5i96 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5i96 RCSB], [http://www.ebi.ac.uk/pdbsum/5i96 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5i96 ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/IDHP_HUMAN IDHP_HUMAN]] D-2-hydroxyglutaric aciduria. Defects in IDH2 are the cause of D-2-hydroxyglutaric aciduria type 2 (D2HGA2) [MIM:[http://omim.org/entry/613657 613657]]. D2HGA2 is a neurometabolic disorder causing developmental delay, epilepsy, hypotonia, and dysmorphic features. Both a mild and a severe phenotype exist. The severe phenotype is homogeneous and is characterized by early infantile-onset epileptic encephalopathy and cardiomyopathy. The mild phenotype has a more variable clinical presentation. Diagnosis is based on the presence of an excess of D-2-hydroxyglutaric acid in the urine.<ref>PMID:20847235</ref>
+[https://www.uniprot.org/uniprot/IDHP_HUMAN IDHP_HUMAN] D-2-hydroxyglutaric aciduria. Defects in IDH2 are the cause of D-2-hydroxyglutaric aciduria type 2 (D2HGA2) [MIM:[https://omim.org/entry/613657 613657]. D2HGA2 is a neurometabolic disorder causing developmental delay, epilepsy, hypotonia, and dysmorphic features. Both a mild and a severe phenotype exist. The severe phenotype is homogeneous and is characterized by early infantile-onset epileptic encephalopathy and cardiomyopathy. The mild phenotype has a more variable clinical presentation. Diagnosis is based on the presence of an excess of D-2-hydroxyglutaric acid in the urine.<ref>PMID:20847235</ref>
 == Function ==
-[[http://www.uniprot.org/uniprot/IDHP_HUMAN IDHP_HUMAN]] Plays a role in intermediary metabolism and energy production. It may tightly associate or interact with the pyruvate dehydrogenase complex.
+[https://www.uniprot.org/uniprot/IDHP_HUMAN IDHP_HUMAN] Plays a role in intermediary metabolism and energy production. It may tightly associate or interact with the pyruvate dehydrogenase complex.
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 29: / Line 28: @@
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: DeLaBarre, B]]
+[[Category: DeLaBarre B]]
-[[Category: Jiang, F]]
+[[Category: Jiang F]]
-[[Category: Jin, L]]
+[[Category: Jin L]]
-[[Category: Padyana, A K]]
+[[Category: Padyana AK]]
-[[Category: Travins, J A]]
+[[Category: Travins JA]]
-[[Category: Wei, W]]
+[[Category: Wei W]]
-[[Category: Zhang, B]]
+[[Category: Zhang B]]
-[[Category: Ag-221]]
-[[Category: Enasidenib]]
-[[Category: Icd-m]]
-[[Category: Idh]]
-[[Category: Idh2]]
-[[Category: Idh2 ag-221]]
-[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]

5i96

From Proteopedia

Current revision

Crystal Structure of Human Mitochondrial Isocitrate Dehydrogenase (IDH2) R140Q Mutant Homodimer in Complex with AG-221 (Enasidenib) Inhibitor.

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox