8P1W

Crystal structure of human methionine adenosyltransferase 2A (MAT2A) in complex with allosteric compound STL232591

PDB DOI: https://doi.org/10.2210/pdb8P1W/pdb

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

Deposited: 2023-05-12 Released: 2023-08-30
Deposition Author(s): Thomsen, M., Thieulin-Pardo, G., Neumann, L.
Funding Organization(s): Not funded

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.15 Å
R-Value Free: 0.129
R-Value Work: 0.112

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.1 of the entry. See complete history.

Literature

Discovery of novel methionine adenosyltransferase 2A (MAT2A) allosteric inhibitors by structure-based virtual screening.

Kalliokoski, T., Kettunen, H., Kumpulainen, E., Kettunen, E., Thieulin-Pardo, G., Neumann, L., Thomsen, M., Paul, R., Malyutina, A., Georgiadou, M.

(2023) Bioorg Med Chem Lett 94: 129450-129450

PubMed: 37591318 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2023.129450
Primary Citation of Related Structures:
8P1T, 8P1V, 8P1W, 8P4H

PubMed Abstract:
Methionine adenosyltransferase 2A (MAT2A) has been indicated as a drug target for oncology indications. Clinical trials with MAT2A inhibitors are currently on-going. Here, a structure-based virtual screening campaign was performed on the commercially available chemical space which yielded two novel MAT2A-inhibitor chemical series. The binding modes of the compounds were confirmed with X-ray crystallography. Both series have acceptable physicochemical properties and show nanomolar activity in the biochemical MAT2A inhibition assay and single-digit micromolar activity in the proliferation assay (MTAP -/- cell line). The identified compounds and the relating structural data could be helpful in related drug discovery projects.

Organizational Affiliation

Orion Pharma, Orionintie 1A, 02101 Espoo, Finland. Electronic address: [email protected].

Macromolecule Content

Total Structure Weight: 46.86 kDa
Atom Count: 3,599
Modelled Residue Count: 381
Deposited Residue Count: 412
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
S-adenosylmethionine synthase isoform type-2	A [auth AAA]	412	Homo sapiens	Mutation(s): 0 Gene Names: MAT2A, AMS2, MATA2 EC: 2.5.1.6
UniProt & NIH Common Fund Data Resources
Find proteins for P31153 (Homo sapiens) Explore P31153 Go to UniProtKB: P31153
PHAROS: P31153 GTEx: ENSG00000168906
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P31153
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 5 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
WK5 (Subject of Investigation/LOI) Query on WK5 Download Ideal Coordinates CCD File SDF format, chain D [auth AAA] MOL2 format, chain D [auth AAA] mmCIF format, chain D [auth AAA]	D [auth AAA]	8-methoxy-1-(4-methoxyphenyl)-3-methyl-2-oxidanyl-[1]benzofuro[3,2-c]pyridine C₂₀ H₁₈ N O₄ KFTZMBXBOCZEMA-UHFFFAOYSA-N		Interactions Focus chain D [auth AAA] Interactions & Density Focus chain D [auth AAA]
MTA Query on MTA Download Ideal Coordinates CCD File SDF format, chain B [auth AAA] MOL2 format, chain B [auth AAA] mmCIF format, chain B [auth AAA]	B [auth AAA]	5'-DEOXY-5'-METHYLTHIOADENOSINE C₁₁ H₁₅ N₅ O₃ S WUUGFSXJNOTRMR-IOSLPCCCSA-N		Interactions Focus chain B [auth AAA] Interactions & Density Focus chain B [auth AAA]
ABA Query on ABA Download Ideal Coordinates CCD File SDF format, chain C [auth AAA] MOL2 format, chain C [auth AAA] mmCIF format, chain C [auth AAA]	C [auth AAA]	ALPHA-AMINOBUTYRIC ACID C₄ H₉ N O₂ QWCKQJZIFLGMSD-VKHMYHEASA-N		Interactions Focus chain C [auth AAA] Interactions & Density Focus chain C [auth AAA]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain H [auth AAA] SDF format, chain I [auth AAA] SDF format, chain J [auth AAA] SDF format, chain K [auth AAA] SDF format, chain L [auth AAA] MOL2 format, chain H [auth AAA] MOL2 format, chain I [auth AAA] MOL2 format, chain J [auth AAA] MOL2 format, chain K [auth AAA] MOL2 format, chain L [auth AAA] mmCIF format, chain H [auth AAA] mmCIF format, chain I [auth AAA] mmCIF format, chain J [auth AAA] mmCIF format, chain K [auth AAA] mmCIF format, chain L [auth AAA]	H [auth AAA], I [auth AAA], J [auth AAA], K [auth AAA], L [auth AAA]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain H [auth AAA] Focus chain I [auth AAA] Focus chain J [auth AAA] Focus chain K [auth AAA] Focus chain L [auth AAA] Interactions & Density Focus chain H [auth AAA] Focus chain I [auth AAA] Focus chain J [auth AAA] Focus chain K [auth AAA] Focus chain L [auth AAA]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain E [auth AAA] SDF format, chain F [auth AAA] SDF format, chain G [auth AAA] MOL2 format, chain E [auth AAA] MOL2 format, chain F [auth AAA] MOL2 format, chain G [auth AAA] mmCIF format, chain E [auth AAA] mmCIF format, chain F [auth AAA] mmCIF format, chain G [auth AAA]	E [auth AAA], F [auth AAA], G [auth AAA]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain E [auth AAA] Focus chain F [auth AAA] Focus chain G [auth AAA] Interactions & Density Focus chain E [auth AAA] Focus chain F [auth AAA] Focus chain G [auth AAA]