6JIB | pdb_00006jib

Human MTHFD2 in complex with DS44960156

PDB DOI: https://doi.org/10.2210/pdb6JIB/pdb

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

Deposited: 2019-02-20 Released: 2019-06-05
Deposition Author(s): Suzuki, M., Matsui, Y., Kawai, J.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.25 Å
R-Value Free:
0.243 (Depositor), 0.240 (DCC)
R-Value Work:
0.201 (Depositor), 0.200 (DCC)
R-Value Observed:
0.203 (Depositor)

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Structure-Based Design and Synthesis of an Isozyme-Selective MTHFD2 Inhibitor with a Tricyclic Coumarin Scaffold.

Kawai, J., Ota, M., Ohki, H., Toki, T., Suzuki, M., Shimada, T., Matsui, S., Inoue, H., Sugihara, C., Matsuhashi, N., Matsui, Y., Takaishi, S., Nakayama, K.

(2019) ACS Med Chem Lett 10: 893-898

PubMed: 31223444 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acsmedchemlett.9b00069
Primary Citation of Related Structures:
6JIB, 6JID

PubMed Abstract:
Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) plays a key role in one-carbon (1C) metabolism in human mitochondria, and its high expression correlates with poor survival of patients with various types of cancer. An isozyme-selective MTHFD2 inhibitor is highly attractive for potential use in cancer treatment. Herein, we disclose a novel isozyme-selective MTHFD2 inhibitor DS44960156, with a tricyclic coumarin scaffold, which was initially discovered via high-throughput screening (HTS) and improved using structure-based drug design (SBDD). DS44960156 would offer a good starting point for further optimization based on the following features: (1) unprecedented selectivity (>18-fold) for MTHFD2 over MTHFD1, (2) a molecular weight of less than 400, and (3) good ligand efficiency (LE).

Organizational Affiliation

R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.

Macromolecule Content

Total Structure Weight: 72.48 kDa
Atom Count: 4,680
Modelled Residue Count: 587
Deposited Residue Count: 646
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial	A, B	323	Homo sapiens	Mutation(s): 0 Gene Names: MTHFD2, NMDMC EC: 1.5.1.15 (PDB Primary Data), 3.5.4.9 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P13995 (Homo sapiens) Explore P13995 Go to UniProtKB: P13995
PHAROS: P13995 GTEx: ENSG00000065911
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P13995
Sequence Annotations Expand
Reference Sequence LOADING

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
BQF (Subject of Investigation/LOI) Query on BQF Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain I [auth B] SDF format, chain E [auth A] SDF format, chain J [auth B] MOL2 format, chain C [auth A] MOL2 format, chain I [auth B] MOL2 format, chain E [auth A] MOL2 format, chain J [auth B] mmCIF format, chain C [auth A] mmCIF format, chain I [auth B] mmCIF format, chain E [auth A] mmCIF format, chain J [auth B]	C [auth A], E [auth A], I [auth B], J [auth B]	4-(5-oxo-1,5-dihydro-2H-[1]benzopyrano[3,4-c]pyridine-3(4H)-carbonyl)benzoic acid C₂₀ H₁₅ N O₅ OXUKTNZACAKVRG-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain E [auth A] Focus chain I [auth B] Focus chain J [auth B] Interactions & Density Focus chain C [auth A] Focus chain E [auth A] Focus chain I [auth B] Focus chain J [auth B]
PO4 Query on PO4 Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain H [auth A] MOL2 format, chain D [auth A] MOL2 format, chain H [auth A] mmCIF format, chain D [auth A] mmCIF format, chain H [auth A]	D [auth A], H [auth A]	PHOSPHATE ION O₄ P NBIIXXVUZAFLBC-UHFFFAOYSA-K		Interactions Focus chain D [auth A] Focus chain H [auth A] Interactions & Density Focus chain D [auth A] Focus chain H [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain K [auth B] SDF format, chain L [auth B] SDF format, chain G [auth A] SDF format, chain M [auth B] MOL2 format, chain F [auth A] MOL2 format, chain K [auth B] MOL2 format, chain L [auth B] MOL2 format, chain G [auth A] MOL2 format, chain M [auth B] mmCIF format, chain F [auth A] mmCIF format, chain K [auth B] mmCIF format, chain L [auth B] mmCIF format, chain G [auth A] mmCIF format, chain M [auth B]	F [auth A], G [auth A], K [auth B], L [auth B], M [auth B]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Focus chain G [auth A] Focus chain K [auth B] Focus chain L [auth B] Focus chain M [auth B] Interactions & Density Focus chain F [auth A] Focus chain G [auth A] Focus chain K [auth B] Focus chain L [auth B] Focus chain M [auth B]

Binding Affinity Annotations
ID	Source	Binding Affinity
BQF	BindingDB: 6JIB	IC50: 1600 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.25 Å
R-Value Free: 0.243 (Depositor), 0.240 (DCC)
R-Value Work: 0.201 (Depositor), 0.200 (DCC)
R-Value Observed: 0.203 (Depositor)

Space Group: P 6₅

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 116.424	α = 90
b = 116.424	β = 90
c = 113.178	γ = 120

Software Package:

Software Name	Purpose
XDS	data reduction
Aimless	data scaling
REFMAC	refinement
PDB_EXTRACT	data extraction
PHASER	phasing

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2019-06-05

Deposition Author(s):

Suzuki, M.

Matsui, Y.

Kawai, J.

Revision History (Full details and data files)

Version 1.0: 2019-06-05
Type: Initial release
Version 1.1: 2019-07-10
Changes: Data collection, Database references
Version 1.2: 2023-11-22
Changes: Data collection, Database references, Refinement description