3T3Q

Human Cytochrome P450 2A6 I208S/I300F/G301A/S369G in complex with Pilocarpine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.257 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.214 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structural comparison of cytochromes P450 2A6, 2A13, and 2E1 with pilocarpine.

DeVore, N.M.Meneely, K.M.Bart, A.G.Stephens, E.S.Battaile, K.P.Scott, E.E.

(2012) FEBS J 279: 1621-1631

  • DOI: https://doi.org/10.1111/j.1742-4658.2011.08412.x
  • Primary Citation of Related Structures:  
    3T3Q, 3T3R, 3T3S, 3T3Z

  • PubMed Abstract: 

    Human xenobiotic-metabolizing cytochrome P450 (CYP) enzymes can each bind and monooxygenate a diverse set of substrates, including drugs, often producing a variety of metabolites. Additionally, a single ligand can interact with multiple CYP enzymes, but often the protein structural similarities and differences that mediate such overlapping selectivity are not well understood. Even though the CYP superfamily has a highly canonical global protein fold, there are large variations in the active site size, topology, and conformational flexibility. We have determined how a related set of three human CYP enzymes bind and interact with a common inhibitor, the muscarinic receptor agonist drug pilocarpine. Pilocarpine binds and inhibits the hepatic CYP2A6 and respiratory CYP2A13 enzymes much more efficiently than the hepatic CYP2E1 enzyme. To elucidate key residues involved in pilocarpine binding, crystal structures of CYP2A6 (2.4 Å), CYP2A13 (3.0 Å), CYP2E1 (2.35 Å), and the CYP2A6 mutant enzyme, CYP2A6 I208S/I300F/G301A/S369G (2.1 Å) have been determined with pilocarpine in the active site. In all four structures, pilocarpine coordinates to the heme iron, but comparisons reveal how individual residues lining the active sites of these three distinct human enzymes interact differently with the inhibitor pilocarpine.


  • Organizational Affiliation

    Department of Medicinal Chemistry, The University of Kansas, Lawrence, KS 66045, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cytochrome P450 2A6
A, B, C, D
476Homo sapiensMutation(s): 4 
Gene Names: CYP2A3CYP2A6CYP2A6 I208S/I300F/G301A/S369G
EC: 1.14.14.1
UniProt & NIH Common Fund Data Resources
Find proteins for P11509 (Homo sapiens)
Explore P11509 
Go to UniProtKB:  P11509
PHAROS:  P11509
GTEx:  ENSG00000255974 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP11509
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
9PL Binding MOAD:  3T3Q Ki: 4.90e+4 (nM) from 1 assay(s)
BindingDB:  3T3Q Ki: min: 1400, max: 3000 (nM) from 2 assay(s)
Kd: min: 3000, max: 3600 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.257 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.214 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 70.952α = 90
b = 159.836β = 91.79
c = 103.855γ = 90
Software Package:
Software NamePurpose
Blu-Icedata collection
PHASERphasing
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: 2011-12-07
    Type: Initial release
  • Version 1.1: 2012-06-06
    Changes: Database references
  • Version 1.2: 2017-11-08
    Changes: Refinement description
  • Version 1.3: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description