3H0W

Human AdoMetDC with 5'-Deoxy-5'-[(N-dimethyl)amino]-8-methyl-adenosine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.81 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.196 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 2.0 of the entry. See complete history


Literature

Role of the sulfonium center in determining the ligand specificity of human s-adenosylmethionine decarboxylase.

Bale, S.Brooks, W.Hanes, J.W.Mahesan, A.M.Guida, W.C.Ealick, S.E.

(2009) Biochemistry 48: 6423-6430

  • DOI: https://doi.org/10.1021/bi900590m
  • Primary Citation of Related Structures:  
    3H0V, 3H0W

  • PubMed Abstract: 

    S-Adenosylmethionine decarboxylase (AdoMetDC) is a key enzyme in the polyamine biosynthetic pathway. Inhibition of this pathway and subsequent depletion of polyamine levels is a viable strategy for cancer chemotherapy and for the treatment of parasitic diseases. Substrate analogue inhibitors display an absolute requirement for a positive charge at the position equivalent to the sulfonium of S-adenosylmethionine. We investigated the ligand specificity of AdoMetDC through crystallography, quantum chemical calculations, and stopped-flow experiments. We determined crystal structures of the enzyme cocrystallized with 5'-deoxy-5'-dimethylthioadenosine and 5'-deoxy-5'-(N-dimethyl)amino-8-methyladenosine. The crystal structures revealed a favorable cation-pi interaction between the ligand and the aromatic side chains of Phe7 and Phe223. The estimated stabilization from this interaction is 4.5 kcal/mol as determined by quantum chemical calculations. Stopped-flow kinetic experiments showed that the rate of the substrate binding to the enzyme greatly depends on Phe7 and Phe223, thus supporting the importance of the cation-pi interaction.


  • Organizational Affiliation

    Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
S-adenosylmethionine decarboxylase proenzymeA [auth B]67Homo sapiensMutation(s): 0 
Gene Names: AMD1AMD
EC: 4.1.1.50
UniProt & NIH Common Fund Data Resources
Find proteins for P17707 (Homo sapiens)
Explore P17707 
Go to UniProtKB:  P17707
PHAROS:  P17707
GTEx:  ENSG00000123505 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP17707
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
S-adenosylmethionine decarboxylase proenzymeB [auth A]266Homo sapiensMutation(s): 0 
Gene Names: AMD1AMD
EC: 4.1.1.50
UniProt & NIH Common Fund Data Resources
Find proteins for P17707 (Homo sapiens)
Explore P17707 
Go to UniProtKB:  P17707
PHAROS:  P17707
GTEx:  ENSG00000123505 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP17707
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
N8M BindingDB:  3H0W IC50: 600 (nM) from 1 assay(s)
PDBBind:  3H0W IC50: 600 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.81 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.196 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 99.449α = 90
b = 51.019β = 105.32
c = 68.692γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACTdata extraction
ADSCdata collection
HKL-2000data reduction
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: 2009-06-30
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-11-01
    Changes: Refinement description
  • Version 1.3: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 2.0: 2023-11-15
    Changes: Atomic model, Data collection, Derived calculations