8P4H

Crystal structure of human methionine adenosyltransferase 2A (MAT2A) in complex with SAM and allosteric compound IDEAYA cmpd A

PDB DOI: https://doi.org/10.2210/pdb8P4H/pdb

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

Deposited: 2023-05-21 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: 1.71 Å
R-Value Free: 0.184
R-Value Work: 0.153
R-Value Observed: 0.154

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

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: 185.81 kDa
Atom Count: 13,205
Modelled Residue Count: 1,511
Deposited Residue Count: 1,648
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
S-adenosylmethionine synthase isoform type-2	A, B, C, D	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
SAM Query on SAM Download Ideal Coordinates CCD File SDF format, chain K [auth B] SDF format, chain Q [auth D] MOL2 format, chain K [auth B] MOL2 format, chain Q [auth D] mmCIF format, chain K [auth B] mmCIF format, chain Q [auth D]	K [auth B], Q [auth D]	S-ADENOSYLMETHIONINE C₁₅ H₂₂ N₆ O₅ S MEFKEPWMEQBLKI-FCKMPRQPSA-N		Interactions Focus chain K [auth B] Focus chain Q [auth D] Interactions & Density Focus chain K [auth B] Focus chain Q [auth D]
UM6 (Subject of Investigation/LOI) Query on UM6 Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain L [auth B] SDF format, chain O [auth C] SDF format, chain S [auth D] MOL2 format, chain E [auth A] MOL2 format, chain L [auth B] MOL2 format, chain O [auth C] MOL2 format, chain S [auth D] mmCIF format, chain E [auth A] mmCIF format, chain L [auth B] mmCIF format, chain O [auth C] mmCIF format, chain S [auth D]	E [auth A], L [auth B], O [auth C], S [auth D]	7-chloranyl-4-[(3R)-3-fluoranylpyrrolidin-1-yl]-1-phenyl-quinazolin-2-one C₁₈ H₁₅ Cl F N₃ O GPTUSHRRTGGGTD-CYBMUJFWSA-N		Interactions Focus chain E [auth A] Focus chain L [auth B] Focus chain O [auth C] Focus chain S [auth D] Interactions & Density Focus chain E [auth A] Focus chain L [auth B] Focus chain O [auth C] Focus chain S [auth D]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain N [auth B] SDF format, chain P [auth C] SDF format, chain T [auth D] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain N [auth B] MOL2 format, chain P [auth C] MOL2 format, chain T [auth D] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain N [auth B] mmCIF format, chain P [auth C] mmCIF format, chain T [auth D]	F [auth A] G [auth A] H [auth A] I [auth A] N [auth B] F [auth A], G [auth A], H [auth A], I [auth A], N [auth B], P [auth C], T [auth D]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain N [auth B] Focus chain P [auth C] Focus chain T [auth D] Interactions & Density Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain N [auth B] Focus chain P [auth C] Focus chain T [auth D]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain M [auth B] SDF format, chain U [auth D] MOL2 format, chain M [auth B] MOL2 format, chain U [auth D] mmCIF format, chain M [auth B] mmCIF format, chain U [auth D]	M [auth B], U [auth D]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain M [auth B] Focus chain U [auth D] Interactions & Density Focus chain M [auth B] Focus chain U [auth D]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain R [auth D] SDF format, chain J [auth B] MOL2 format, chain R [auth D] MOL2 format, chain J [auth B] mmCIF format, chain R [auth D] mmCIF format, chain J [auth B]	J [auth B], R [auth D]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain J [auth B] Focus chain R [auth D] Interactions & Density Focus chain J [auth B] Focus chain R [auth D]