5TQH

IDH1 R132H mutant in complex with IDH889

PDB DOI: https://doi.org/10.2210/pdb5TQH/pdb

Classification: OXIDOREDUCTASE
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): Yes

Deposited: 2016-10-24 Released: 2017-01-25
Deposition Author(s): Xie, X., Kulathila, R.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.20 Å
R-Value Free: 0.225
R-Value Work: 0.188
R-Value Observed: 0.189

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Literature

Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Allosteric and Mutant Specific Inhibitors of IDH1.

Levell, J.R., Caferro, T., Chenail, G., Dix, I., Dooley, J., Firestone, B., Fortin, P.D., Giraldes, J., Gould, T., Growney, J.D., Jones, M.D., Kulathila, R., Lin, F., Liu, G., Mueller, A., van der Plas, S., Slocum, K., Smith, T., Terranova, R., Toure, B.B., Tyagi, V., Wagner, T., Xie, X., Xu, M., Yang, F.S., Zhou, L.X., Pagliarini, R., Cho, Y.S.

(2017) ACS Med Chem Lett 8: 151-156

PubMed: 28197303 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acsmedchemlett.6b00334
Primary Citation of Related Structures:
5TQH

PubMed Abstract:
High throughput screening and subsequent hit validation identified 4-isopropyl-3-(2-((1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a potent inhibitor of IDH1 ^R132H. Synthesis of the four separate stereoisomers identified the ( S , S )-diastereomer ( IDH125 , 1f ) as the most potent isomer. This also showed reasonable cellular activity and excellent selectivity vs IDH1 ^wt. Initial structure-activity relationship exploration identified the key tolerances and potential for optimization. X-ray crystallography identified a functionally relevant allosteric binding site amenable to inhibitors, which can penetrate the blood-brain barrier, and aided rational optimization. Potency improvement and modulation of the physicochemical properties identified ( S , S )-oxazolidinone IDH889 ( 5x ) with good exposure and 2-HG inhibitory activity in a mutant IDH1 xenograft mouse model.

Organizational Affiliation

Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.

Macromolecule Content

Total Structure Weight: 193.13 kDa
Atom Count: 13,864
Modelled Residue Count: 1,618
Deposited Residue Count: 1,668
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Isocitrate dehydrogenase [NADP] cytoplasmic	A, B, C, D	417	Homo sapiens	Mutation(s): 1 Gene Names: IDH1, PICD EC: 1.1.1.42
UniProt & NIH Common Fund Data Resources
Find proteins for O75874 (Homo sapiens) Explore O75874 Go to UniProtKB: O75874
PHAROS: O75874 GTEx: ENSG00000138413
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	O75874
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
NDP Query on NDP Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain J [auth B] SDF format, chain M [auth C] SDF format, chain P [auth D] MOL2 format, chain G [auth A] MOL2 format, chain J [auth B] MOL2 format, chain M [auth C] MOL2 format, chain P [auth D] mmCIF format, chain G [auth A] mmCIF format, chain J [auth B] mmCIF format, chain M [auth C] mmCIF format, chain P [auth D]	G [auth A], J [auth B], M [auth C], P [auth D]	NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE C₂₁ H₃₀ N₇ O₁₇ P₃ ACFIXJIJDZMPPO-NNYOXOHSSA-N		Interactions Focus chain G [auth A] Focus chain J [auth B] Focus chain M [auth C] Focus chain P [auth D] Interactions & Density Focus chain G [auth A] Focus chain J [auth B] Focus chain M [auth C] Focus chain P [auth D]
7J2 Query on 7J2 Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain H [auth B] SDF format, chain K [auth C] SDF format, chain N [auth D] MOL2 format, chain F [auth A] MOL2 format, chain H [auth B] MOL2 format, chain K [auth C] MOL2 format, chain N [auth D] mmCIF format, chain F [auth A] mmCIF format, chain H [auth B] mmCIF format, chain K [auth C] mmCIF format, chain N [auth D]	F [auth A], H [auth B], K [auth C], N [auth D]	(4S)-3-[2-({(1S)-1-[5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl]ethyl}amino)pyrimidin-4-yl]-4-(propan-2-yl)-1,3-oxazolidin-2-one C₂₃ H₂₅ F N₆ O₂ JDCYIMQAIKEACU-HNAYVOBHSA-N		Interactions Focus chain F [auth A] Focus chain H [auth B] Focus chain K [auth C] Focus chain N [auth D] Interactions & Density Focus chain F [auth A] Focus chain H [auth B] Focus chain K [auth C] Focus chain N [auth D]
FLC Query on FLC Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain I [auth B] SDF format, chain L [auth C] SDF format, chain O [auth D] MOL2 format, chain E [auth A] MOL2 format, chain I [auth B] MOL2 format, chain L [auth C] MOL2 format, chain O [auth D] mmCIF format, chain E [auth A] mmCIF format, chain I [auth B] mmCIF format, chain L [auth C] mmCIF format, chain O [auth D]	E [auth A], I [auth B], L [auth C], O [auth D]	CITRATE ANION C₆ H₅ O₇ KRKNYBCHXYNGOX-UHFFFAOYSA-K		Interactions Focus chain E [auth A] Focus chain I [auth B] Focus chain L [auth C] Focus chain O [auth D] Interactions & Density Focus chain E [auth A] Focus chain I [auth B] Focus chain L [auth C] Focus chain O [auth D]