5K9C

Crystal structure of human dihydroorotate dehydrogenase with ML390

PDB DOI: https://doi.org/10.2210/pdb5K9C/pdb

Classification: OXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2016-05-31 Released: 2016-10-12
Deposition Author(s): Lewis, T.A., Sykes, D.B., Law, J.M., Munoz, B., Scadden, D.T., Rustiguel, J.K., Nonato, M.C., Schreiber, S.L.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.66 Å
R-Value Free: 0.150
R-Value Work: 0.131
R-Value Observed: 0.132

Starting Model: experimental
View more details

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Development of ML390: A Human DHODH Inhibitor That Induces Differentiation in Acute Myeloid Leukemia.

Lewis, T.A., Sykes, D.B., Law, J.M., Munoz, B., Rustiguel, J.K., Nonato, M.C., Scadden, D.T., Schreiber, S.L.

(2016) ACS Med Chem Lett 7: 1112-1117

PubMed: 27994748 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acsmedchemlett.6b00316
Primary Citation of Related Structures:
5K9C, 5K9D

PubMed Abstract:
Homeobox transcription factor A9 (HoxA9) is overexpressed in 70% of patients diagnosed with acute myeloid leukemia (AML), whereas only a small subset of AML patients respond to current differentiation therapies. A cell line overexpressing HoxA9 was derived from the bone marrow of a lysozyme-GFP mouse. In this fashion, GFP served as an endogenous reporter of differentiation, permitting a high-throughput phenotypic screen against the MLPCN library. Two chemical scaffolds were optimized for activity yielding compound ML390, and genetic resistance and sequencing efforts identified dihydroorotate dehydrogenase (DHODH) as the target enzyme. The DHODH inhibitor brequinar works against these leukemic cells as well. The X-ray crystal structure of ML390 bound to DHODH elucidates ML390s binding interactions.

Organizational Affiliation

Center for the Science of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.

Macromolecule Content

Total Structure Weight: 41.5 kDa
Atom Count: 3,271
Modelled Residue Count: 355
Deposited Residue Count: 368
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Dihydroorotate dehydrogenase (quinone), mitochondrial	A	368	Homo sapiens	Mutation(s): 0 Gene Names: DHODH EC: 1.3.5.2
UniProt & NIH Common Fund Data Resources
Find proteins for Q02127 (Homo sapiens) Explore Q02127 Go to UniProtKB: Q02127
PHAROS: Q02127 GTEx: ENSG00000102967
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q02127
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 7 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
FNR Query on FNR Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A] mmCIF format, chain B [auth A]	B [auth A]	1-DEOXY-1-(7,8-DIMETHYL-2,4-DIOXO-3,4-DIHYDRO-2H-BENZO[G]PTERIDIN-1-ID-10(5H)-YL)-5-O-PHOSPHONATO-D-RIBITOL C₁₇ H₂₃ N₄ O₉ P YTNIXZGTHTVJBW-SCRDCRAPSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]
MLJ Query on MLJ Download Ideal Coordinates CCD File SDF format, chain D [auth A] MOL2 format, chain D [auth A] mmCIF format, chain D [auth A]	D [auth A]	~{N}-[3-oxidanylidene-3-[[(1~{R})-1,2,3,4-tetrahydronaphthalen-1-yl]amino]propyl]-4-(trifluoromethyloxy)benzamide C₂₁ H₂₁ F₃ N₂ O₃ SGNRHEDBLPGDDC-GOSISDBHSA-N		Interactions Focus chain D [auth A] Interactions & Density Focus chain D [auth A]
ORO Query on ORO Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A] mmCIF format, chain C [auth A]	C [auth A]	OROTIC ACID C₅ H₄ N₂ O₄ PXQPEWDEAKTCGB-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain F [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A]	E [auth A], F [auth A]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain E [auth A] Focus chain F [auth A] Interactions & Density Focus chain E [auth A] Focus chain F [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain L [auth A] MOL2 format, chain L [auth A] mmCIF format, chain L [auth A]	L [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain L [auth A] Interactions & Density Focus chain L [auth A]
ACT Query on ACT Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain I [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A]	G [auth A], H [auth A], I [auth A]	ACETATE ION C₂ H₃ O₂ QTBSBXVTEAMEQO-UHFFFAOYSA-M		Interactions Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Interactions & Density Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain J [auth A] SDF format, chain K [auth A] MOL2 format, chain J [auth A] MOL2 format, chain K [auth A] mmCIF format, chain J [auth A] mmCIF format, chain K [auth A]	J [auth A], K [auth A]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain J [auth A] Focus chain K [auth A] Interactions & Density Focus chain J [auth A] Focus chain K [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
MLJ	BindingDB: 5K9C	IC50: 560 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.66 Å
R-Value Free: 0.150
R-Value Work: 0.131
R-Value Observed: 0.132
Space Group: P 3₂ 2 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 89.9	α = 90
b = 89.9	β = 90
c = 121.771	γ = 120

Software Package:

Software Name	Purpose
iMOSFLM	data reduction
SCALA	data scaling
PHASER	phasing
PHENIX	refinement
PDB_EXTRACT	data extraction

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2016-10-12

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2016-10-12
Type: Initial release
Version 1.1: 2017-01-04
Changes: Database references
Version 1.2: 2023-09-27
Changes: Data collection, Database references, Refinement description

Prepare Data

Validate Data

Deposit Data

Help and Resources

5K9C

Crystal structure of human dihydroorotate dehydrogenase with ML390

Development of ML390: A Human DHODH Inhibitor That Induces Differentiation in Acute Myeloid Leukemia.

Entity ID: 1

UniProt & NIH Common Fund Data Resources

Entity Groups

Sequence Annotations

Expand

Experimental Data

Structure Validation

Ligand Structure Quality Assessment

Deposition Data

Revision History (Full details and data files)