7RW7

Crystal structure of human methionine adenosyltransferase 2A (MAT2A) in complex with SAM and allosteric inhibitor Compound 9


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.19 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.201 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Leveraging Structure-Based Drug Design to Identify Next-Generation MAT2A Inhibitors, Including Brain-Penetrant and Peripherally Efficacious Leads.

Li, M.Konteatis, Z.Nagaraja, N.Chen, Y.Zhou, S.Ma, G.Gross, S.Marjon, K.Hyer, M.L.Mandley, E.Lein, M.Padyana, A.K.Jin, L.Tong, S.Peters, R.Murtie, J.Travins, J.Medeiros, M.Liu, P.Frank, V.Judd, E.T.Biller, S.A.Marks, K.M.Sui, Z.Reznik, S.K.

(2022) J Med Chem 65: 4600-4615

  • DOI: https://doi.org/10.1021/acs.jmedchem.1c01595
  • Primary Citation of Related Structures:  
    7RW5, 7RW7, 7RWG, 7RWH

  • PubMed Abstract: 

    Inhibition of the S -adenosyl methionine (SAM)-producing metabolic enzyme, methionine adenosyltransferase 2A (MAT2A), has received significant interest in the field of medicinal chemistry due to its implication as a synthetic lethal target in cancers with the deletion of the methylthioadenosine phosphorylase (MTAP) gene. Here, we report the identification of novel MAT2A inhibitors with distinct in vivo properties that may enhance their utility in treating patients. Following a high-throughput screening, we successfully applied the structure-based design lessons from our first-in-class MAT2A inhibitor, AG-270 , to rapidly redesign and optimize our initial hit into two new lead compounds: a brain-penetrant compound, AGI-41998 , and a potent, but limited brain-penetrant compound, AGI-43192 . We hope that the identification and first disclosure of brain-penetrant MAT2A inhibitors will create new opportunities to explore the potential therapeutic effects of SAM modulation in the central nervous system (CNS).


  • Organizational Affiliation

    Agios Pharmaceuticals, Inc., 88 Sidney Street, Cambridge, Massachusetts 02139, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
S-adenosylmethionine synthase isoform type-2396Homo sapiensMutation(s): 0 
Gene Names: MAT2AAMS2MATA2
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 Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP31153
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
7UB (Subject of Investigation/LOI)
Query on 7UB

Download Ideal Coordinates CCD File 
J [auth A](3'R)-2-[(cyclopropylmethyl)amino]-6-(4-methoxyphenyl)-1'-[(1H-pyrazol-5-yl)methyl]-5,6-dihydro-7H-spiro[pyrido[4,3-d]pyrimidine-8,3'-pyrrolidin]-7-one
C25 H29 N7 O2
CBHUSCSYQHQLDW-RUZDIDTESA-N
SAM
Query on SAM

Download Ideal Coordinates CCD File 
B [auth A]S-ADENOSYLMETHIONINE
C15 H22 N6 O5 S
MEFKEPWMEQBLKI-FCKMPRQPSA-N
PEG
Query on PEG

Download Ideal Coordinates CCD File 
I [auth A]DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
D [auth A],
F [auth A],
G [auth A],
H [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
C [auth A],
E [auth A]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.19 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.201 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 68.102α = 90
b = 93.997β = 90
c = 116.356γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Other private--

Revision History  (Full details and data files)

  • Version 1.0: 2022-03-23
    Type: Initial release
  • Version 1.1: 2022-03-30
    Changes: Database references
  • Version 1.2: 2022-04-06
    Changes: Database references
  • Version 1.3: 2023-10-18
    Changes: Data collection, Refinement description