6u4j

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of IDH1 R132H mutant in complex with FT-2102

Structural highlights

6u4j 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 2.11Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

IDHC_HUMAN Defects in IDH1 are involved in the development of glioma (GLM) [MIM: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

IDHC_HUMAN

Publication Abstract from PubMed

Inhibition of mutant IDH1 is being evaluated clinically as a treatment option for oncology. Here we describe the structure-based design and optimization of quinoline lead compounds to identify FT-2102, a potent, orally bioavailable, brain penetrant, and selective mIDH1 inhibitor. FT-2102 has excellent ADME/PK properties and reduces 2-hydroxyglutarate levels in an mIDH1 xenograft tumor model. This compound has been selected as a candidate for clinical development in hematologic malignancies, solid tumors, and gliomas with mIDH1.

Structure-Based Design and Identification of FT-2102 (Olutasidenib), a Potent Mutant-Selective IDH1 Inhibitor.,Caravella JA, Lin J, Diebold RB, Campbell AM, Ericsson A, Gustafson G, Wang Z, Castro J, Clarke A, Gotur D, Josephine HR, Katz M, Kershaw M, Yao L, Toms AV, Barr KJ, Dinsmore CJ, Walker D, Ashwell S, Lu W J Med Chem. 2020 Feb 27;63(4):1612-1623. doi: 10.1021/acs.jmedchem.9b01423. Epub , 2020 Feb 12. PMID:31971798^[1]

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

References

↑ Caravella JA, Lin J, Diebold RB, Campbell AM, Ericsson A, Gustafson G, Wang Z, Castro J, Clarke A, Gotur D, Josephine HR, Katz M, Kershaw M, Yao L, Toms AV, Barr KJ, Dinsmore CJ, Walker D, Ashwell S, Lu W. Structure-Based Design and Identification of FT-2102 (Olutasidenib), a Potent Mutant-Selective IDH1 Inhibitor. J Med Chem. 2020 Feb 27;63(4):1612-1623. doi: 10.1021/acs.jmedchem.9b01423. Epub , 2020 Feb 12. PMID:31971798 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b01423

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/6u4j"

Categories: Homo sapiens | Large Structures | Lin J | Toms AV

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6u4j is ON HOLD
+==Crystal structure of IDH1 R132H mutant in complex with FT-2102==
+<StructureSection load='6u4j' size='340' side='right'caption='[[6u4j]], [[Resolution|resolution]] 2.11&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6u4j]] 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=6U4J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6U4J 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]] 2.11&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FLC:CITRATE+ANION'>FLC</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=PWV:5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile'>PWV</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=6u4j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6u4j OCA], [https://pdbe.org/6u4j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6u4j RCSB], [https://www.ebi.ac.uk/pdbsum/6u4j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6u4j 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 ==
+Inhibition of mutant IDH1 is being evaluated clinically as a treatment option for oncology. Here we describe the structure-based design and optimization of quinoline lead compounds to identify FT-2102, a potent, orally bioavailable, brain penetrant, and selective mIDH1 inhibitor. FT-2102 has excellent ADME/PK properties and reduces 2-hydroxyglutarate levels in an mIDH1 xenograft tumor model. This compound has been selected as a candidate for clinical development in hematologic malignancies, solid tumors, and gliomas with mIDH1.
-Authors: Toms, A.V., Lin, J.
+Structure-Based Design and Identification of FT-2102 (Olutasidenib), a Potent Mutant-Selective IDH1 Inhibitor.,Caravella JA, Lin J, Diebold RB, Campbell AM, Ericsson A, Gustafson G, Wang Z, Castro J, Clarke A, Gotur D, Josephine HR, Katz M, Kershaw M, Yao L, Toms AV, Barr KJ, Dinsmore CJ, Walker D, Ashwell S, Lu W J Med Chem. 2020 Feb 27;63(4):1612-1623. doi: 10.1021/acs.jmedchem.9b01423. Epub , 2020 Feb 12. PMID:31971798<ref>PMID:31971798</ref>
-Description: Crystal structure of IDH1 R132H mutant in complex with FT-2102
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Lin, J]]
+<div class="pdbe-citations 6u4j" style="background-color:#fffaf0;"></div>
-[[Category: Toms, A.V]]
+==See Also==
+*[[Isocitrate dehydrogenase 3D structures|Isocitrate dehydrogenase 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Lin J]]
+[[Category: Toms AV]]

6u4j

From Proteopedia

Current revision

Crystal structure of IDH1 R132H mutant in complex with FT-2102

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