This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.

6bl1

From Proteopedia

(Difference between revisions)

Jump to: navigation, search

Revision as of 06:33, 22 August 2018

Novel Modes of Inhibition of Wild-Type IDH1: Direct Covalent Modification of His315 with Cmpd13

Structural highlights

6bl1 is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Gene:	IDH1, PICD (HUMAN)
Activity:	Isocitrate dehydrogenase (NADP(+)), with EC number 1.1.1.42
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.

Publication Abstract from PubMed

IDH1 plays a critical role in a number of metabolic processes and serves as a key source of cytosolic NADPH under conditions of cellular stress. However, few inhibitors of wild-type IDH1 have been reported. Here we present the discovery and biochemical characterization of two novel inhibitors of wild-type IDH1. In addition, we present the first ligand-bound crystallographic characterization of these novel small molecule IDH1 binding pockets. Importantly, the NADPH competitive ,-unsaturated enone 1 makes a unique covalent linkage through active site H315. As few small molecules have been shown to covalently react with histidine residues, these data support the potential utility of an underutilized strategy for reversible covalent small molecule design.

Novel Modes of Inhibition of Wild-Type Isocitrate Dehydrogenase 1 (IDH1): Direct Covalent Modification of His315.,Jakob CG, Upadhyay AK, Donner PL, Nicholl E, Addo SN, Qiu W, Ling C, Gopalakrishnan SM, Torrent M, Cepa SP, Shanley J, Shoemaker AR, Sun CC, Vasudevan A, Woller KR, Shotwell JB, Shaw B, Bian Z, Hutti JE J Med Chem. 2018 Jul 13. doi: 10.1021/acs.jmedchem.8b00305. PMID:30004704^[1]

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

References

↑ Jakob CG, Upadhyay AK, Donner PL, Nicholl E, Addo SN, Qiu W, Ling C, Gopalakrishnan SM, Torrent M, Cepa SP, Shanley J, Shoemaker AR, Sun CC, Vasudevan A, Woller KR, Shotwell JB, Shaw B, Bian Z, Hutti JE. Novel Modes of Inhibition of Wild-Type Isocitrate Dehydrogenase 1 (IDH1): Direct Covalent Modification of His315. J Med Chem. 2018 Jul 13. doi: 10.1021/acs.jmedchem.8b00305. PMID:30004704 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b00305

1 Structural highlights
2 Disease
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6bl1"

@@ Line 3: / Line 3: @@
 <StructureSection load='6bl1' size='340' side='right' caption='[[6bl1]], [[Resolution|resolution]] 2.02&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6bl1]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BL1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BL1 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6bl1]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BL1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BL1 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=DWG:(6aS,7S,9S,10aS)-7-methyl-8-oxo-10a-phenyl-2-(phenylamino)-5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazoline-9-carbonitrile'>DWG</scene>, <scene name='pdbligand=ICT:ISOCITRIC+ACID'>ICT</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IDH1, PICD ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6bl1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bl1 OCA], [http://pdbe.org/6bl1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bl1 RCSB], [http://www.ebi.ac.uk/pdbsum/6bl1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bl1 ProSAT]</span></td></tr>
@@ Line 23: / Line 24: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Jakob, C G]]
 [[Category: Qiu, W]]

6bl1

From Proteopedia

Revision as of 06:33, 22 August 2018

Novel Modes of Inhibition of Wild-Type IDH1: Direct Covalent Modification of His315 with Cmpd13

Structural highlights

Disease

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox