1Y6Q

Cyrstal structure of MTA/AdoHcy nucleosidase complexed with MT-DADMe-ImmA


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.198 

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Literature

Structural rationale for the affinity of pico- and femtomolar transition state analogues of Escherichia coli 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase.

Lee, J.E.Singh, V.Evans, G.B.Tyler, P.C.Furneaux, R.H.Cornell, K.A.Riscoe, M.K.Schramm, V.L.Howell, P.L.

(2005) J Biol Chem 280: 18274-18282

  • DOI: https://doi.org/10.1074/jbc.M414471200
  • Primary Citation of Related Structures:  
    1Y6Q, 1Y6R

  • PubMed Abstract: 

    Immucillin and DADMe-Immucillin inhibitors are tight binding transition state mimics of purine nucleoside phosphorylases (PNP). 5'-Methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) is proposed to form a similar transition state structure as PNP. The companion paper describes modifications of the Immucillin and DADMe-Immucillin inhibitors to better match transition state features of MTAN and have led to 5'-thio aromatic substitutions that extend the inhibition constants to the femtomolar range (Singh, V., Evans, G. B., Lenz, D. H., Mason, J., Clinch, K., Mee, S., Painter, G. F., Tyler, P. C., Furneaux, R. H., Lee, J. E., Howell, P. L., and Schramm, V. L. (2005) J. Biol. Chem. 280, 18265-18273). 5'-Methylthio-Immucillin A (MT-ImmA) and 5'-methylthio-DADMe-Immucillin A (MT-DADMe-ImmA) exhibit slow-onset inhibition with K(i)(*) of 77 and 2 pm, respectively, and were selected for structural analysis as the parent compounds of each class of transition state analogue. The crystal structures of Escherichia coli MTAN complexed with MT-ImmA and MT-DADMe-ImmA were determined to 2.2 A resolution and compared with the existing MTAN inhibitor complexes. These MTAN-transition state complexes are among the tightest binding enzyme-ligand complexes ever described and analysis of their mode of binding provides extraordinary insight into the structural basis for their affinity. The MTAN-MT-ImmA complex reveals the presence of a new ion pair between the 4'-iminoribitol atom and the nucleophilic water (WAT3) that captures key features of the transition state. Similarly, in the MTAN-MT-DADMe-ImmA complex a favorable hydrogen bond or ion pair interaction between the cationic 1'-pyrrolidine atom and WAT3 is crucial for tight affinity. Distance analysis of the nucleophile and leaving group show that MT-ImmA is a mimic of an early transition state, while MT-DADMe-ImmA is a better mimic of the highly dissociated transition state of E. coli MTAN.


  • Organizational Affiliation

    Structural Biology and Biochemistry, Research Institute, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
MTA/SAH nucleosidase
A, B
242Escherichia coliMutation(s): 0 
Gene Names: mtnNmtnpfs
EC: 3.2.2.16 (PDB Primary Data), 3.2.2.9 (PDB Primary Data)
UniProt
Find proteins for P0AF12 (Escherichia coli (strain K12))
Explore P0AF12 
Go to UniProtKB:  P0AF12
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP0AF12
Sequence Annotations
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
TDI BindingDB:  1Y6Q Ki: min: 2.00e-3, max: 0.07 (nM) from 4 assay(s)
Kd: min: 2.00e-3, max: 0.78 (nM) from 2 assay(s)
Binding MOAD:  1Y6Q Ki: 2.00e-3 (nM) from 1 assay(s)
PDBBind:  1Y6Q Ki: 2.00e-3 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.198 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 51.71α = 90
b = 69.79β = 90
c = 128.34γ = 90
Software Package:
Software NamePurpose
CNSrefinement
CrystalCleardata reduction
d*TREKdata scaling
CNSphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2005-03-01
    Type: Initial release
  • Version 1.1: 2008-04-30
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-08-23
    Changes: Data collection, Database references, Derived calculations, Refinement description