4F2W

Crystal structure of 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase from Salmonella enterica with methyl-thio-DADMe-Immucillin-A


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.179 

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Literature

Crystal structure of 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase from Salmonella enterica with methyl-thio-DADMe-Immucillin-A

Haapalainen, A.M.Thomas, K.Tyler, P.C.Evans, G.B.Almo, S.C.Schramm, V.L.

(2013) Structure 21: 963-974

  • DOI: https://doi.org/10.1016/j.str.2013.04.009
  • Primary Citation of Related Structures:  
    4F1W, 4F2P, 4F2W, 4F3C, 4F3K

  • PubMed Abstract: 

    Accumulation of 5'-methylthioadenosine (MTA) and S-adenosylhomocysteine (SAH) in bacteria disrupts the S-adenosylmethionine pool to alter biological methylations, synthesis of polyamines, and production of quorum-sensing molecules. Bacterial metabolism of MTA and SAH depends on MTA/SAH nucleosidase (MTAN), an enzyme not present in humans and a target for quorum sensing because MTAN activity is essential for synthesis of autoinducer-2 molecules. Crystals of Salmonella enterica MTAN with product and transition state analogs of MTA and SAH explain the structural contacts causing pM binding affinity for the inhibitor and reveal a "water-wire" channel for the catalytic nucleophile. The crystal structure shows an extension of the binding pocket filled with polyethylene glycol. We exploited this discovery by the design and synthesis of tailored modifications of the currently existing transition state analogs to fill this site. This site was not anticipated in MTAN structures. Tailored inhibitors with dissociation constants of 5 to 15 pM are characterized.


  • Organizational Affiliation

    Department of Biochemistry, Albert Einstein College of Medicine of Yeshiva University, 1300 Morris Park Avenue, Bronx, NY 10461, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase
A, B
248Salmonella enterica subsp. enterica serovar Choleraesuis str. SCSA50Mutation(s): 0 
Gene Names: EMBL EFZ04802.1mtnNpfsSCA50_0219SCH_0207
EC: 3.2.2.9
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
TDI
Query on TDI

Download Ideal Coordinates CCD File 
C [auth A],
H [auth B]
(3R,4S)-1-[(4-AMINO-5H-PYRROLO[3,2-D]PYRIMIDIN-7-YL)METHYL]-4-[(METHYLSULFANYL)METHYL]PYRROLIDIN-3-OL
C13 H19 N5 O S
NTHMDFGHOCNNOE-ZJUUUORDSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
D [auth A]
E [auth A]
F [auth A]
I [auth B]
J [auth B]
D [auth A],
E [auth A],
F [auth A],
I [auth B],
J [auth B],
K [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
G [auth A],
L [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
TDI PDBBind:  4F2W Ki: 5.00e-3 (nM) from 1 assay(s)
BindingDB:  4F2W Ki: min: 2.00e-3, max: 0.07 (nM) from 3 assay(s)
Kd: min: 2.00e-3, max: 0.78 (nM) from 2 assay(s)
Binding MOAD:  4F2W Ki: 5.00e-3 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.179 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 69.41α = 90
b = 82.54β = 90
c = 93.11γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
MOLREPphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-05-01
    Type: Initial release
  • Version 1.1: 2013-06-19
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations