7RXW

Human Methionine Adenosyltransferase 2A bound to Methylthioadenosine and inhibitor imido-diphosphate (PNP)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.07 Å
  • R-Value Free: 0.138 
  • R-Value Work: 0.128 
  • R-Value Observed: 0.128 

Starting Model: experimental
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This is version 1.2 of the entry. See complete history


Literature

Mechanism of Triphosphate Hydrolysis by Human MAT2A at 1.07 angstrom Resolution.

Ghosh, A.Niland, C.N.Cahill, S.M.Karadkhelkar, N.M.Schramm, V.L.

(2021) J Am Chem Soc 143: 18325-18330

  • DOI: https://doi.org/10.1021/jacs.1c09328
  • Primary Citation of Related Structures:  
    7RXV, 7RXW, 7RXX

  • PubMed Abstract: 

    Human methionine adenosyltransferase MAT2A provides S -adenosyl-l-methionine (AdoMet) for methyl-transfer reactions. Epigenetic methylations influence expression patterns in development and in cancer. Transition-state analysis and kinetic studies have described the mechanism of AdoMet and triphosphate formation at the catalytic site. Hydrolysis of triphosphate to pyrophosphate and phosphate by MAT2A is required for product release and proceeds through a second chemical transition state. Crystal structures of MAT2A with analogues of AdoMet and pyrophosphate were obtained in the presence of Mg 2+ , Al 3+ , and F - . MgF 3 - is trapped as a PO 3 - mimic in a structure with malonate filling the pyrophosphate site. NMR demonstrates that MgF 3 - and AlF 3 0 are bound by MAT2A as mimics of the departing phosphoryl group. Crystallographic analysis reveals a planar MgF 3 - acting to mimic a phosphoryl (PO 3 - ) leaving group. The modeled transition state with PO 3 - has the phosphorus atom sandwiched symmetrically and equidistant (approximately 2 Å) between a pyrophosphate oxygen and the water nucleophile. A catalytic site arginine directs the nucleophilic water to the phosphoryl leaving group. The catalytic geometry of the transition-state reconstruction predicts a loose transition state with characteristics of symmetric nucleophilic displacement.


  • Organizational Affiliation

    Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
S-adenosylmethionine synthase isoform type-2417Homo 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
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  • Reference Sequence
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
MTA (Subject of Investigation/LOI)
Query on MTA

Download Ideal Coordinates CCD File 
B [auth A]5'-DEOXY-5'-METHYLTHIOADENOSINE
C11 H15 N5 O3 S
WUUGFSXJNOTRMR-IOSLPCCCSA-N
2PN (Subject of Investigation/LOI)
Query on 2PN

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D [auth A]IMIDODIPHOSPHORIC ACID
H5 N O6 P2
GNGSOPFGGKKDQP-UHFFFAOYSA-N
ALA
Query on ALA

Download Ideal Coordinates CCD File 
C [auth A]ALANINE
C3 H7 N O2
QNAYBMKLOCPYGJ-REOHCLBHSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
E [auth A]1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
K (Subject of Investigation/LOI)
Query on K

Download Ideal Coordinates CCD File 
H [auth A]POTASSIUM ION
K
NPYPAHLBTDXSSS-UHFFFAOYSA-N
MG (Subject of Investigation/LOI)
Query on MG

Download Ideal Coordinates CCD File 
F [auth A],
G [auth A]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.07 Å
  • R-Value Free: 0.138 
  • R-Value Work: 0.128 
  • R-Value Observed: 0.128 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 68.322α = 90
b = 94.069β = 90
c = 117.344γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesGM041916
National Institutes of Health/National Cancer Institute (NIH/NCI)United StatesCA013330

Revision History  (Full details and data files)

  • Version 1.0: 2021-11-10
    Type: Initial release
  • Version 1.1: 2021-11-17
    Changes: Database references
  • Version 1.2: 2023-10-18
    Changes: Data collection, Refinement description