4I91

Crystal Structure of Cytochrome P450 2B6 (Y226H/K262R) in complex with alpha-Pinene.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.183 

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Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Structural and Thermodynamic Basis of (+)-alpha-Pinene Binding to Human Cytochrome P450 2B6.

Wilderman, P.R.Shah, M.B.Jang, H.H.Stout, C.D.Halpert, J.R.

(2013) J Am Chem Soc 135: 10433-10440

  • DOI: https://doi.org/10.1021/ja403042k
  • Primary Citation of Related Structures:  
    4I91

  • PubMed Abstract: 

    Despite recent advances in atomic-level understanding of drug and inhibitor interactions with human cytochromes P450, the decades-old questions of chemical and structural determinants of hydrocarbon binding are still unanswered. (+)-α-Pinene is a monoterpene hydrocarbon that is widely distributed in the environment and a potent P450 2B inhibitor. Therefore, a combined biophysical and structural analysis of human P450 2B6 interactions with (+)-α-pinene was undertaken to elucidate the basis of the very high affinity binding. Binding of (+)-α-pinene to the P450 active site was demonstrated by a Type I spectral shift. Thermodynamics of ligand binding were explored using isothermal titration calorimetry and compared to those of P450 2A6, which is much less flexible than 2B6 based on comparison of multiple X-ray crystal structures. Consistent with expectation, entropy is the major driving force for hydrocarbon binding to P450 2A6, as evidenced by the calorimetric results. However, formation of the 2B6-(+)-α-pinene complex has a significant enthalpic component. A 2.0 Å resolution crystal structure of this enzyme-ligand complex reveals that the highly plastic 2B6 utilizes previously unrecognized rearrangements of protein motifs. The results indicate that the specific components of enthalpic contribution to ligand binding are closely tied to the degree of enzyme flexibility.


  • Organizational Affiliation

    Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, United States. pwilderman@ucsd.edu


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cytochrome P450 2B6476Homo sapiensMutation(s): 11 
Gene Names: CYP2B6
EC: 1.14.13
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P20813 (Homo sapiens)
Explore P20813 
Go to UniProtKB:  P20813
PHAROS:  P20813
GTEx:  ENSG00000197408 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP20813
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HEM
Query on HEM

Download Ideal Coordinates CCD File 
B [auth A]PROTOPORPHYRIN IX CONTAINING FE
C34 H32 Fe N4 O4
KABFMIBPWCXCRK-RGGAHWMASA-L
CM5
Query on CM5

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A],
F [auth A]
5-CYCLOHEXYL-1-PENTYL-BETA-D-MALTOSIDE
C23 H42 O11
RVTGFZGNOSKUDA-ZNGNCRBCSA-N
FRU
Query on FRU

Download Ideal Coordinates CCD File 
C [auth A]beta-D-fructofuranose
C6 H12 O6
RFSUNEUAIZKAJO-ARQDHWQXSA-N
TMH
Query on TMH

Download Ideal Coordinates CCD File 
G [auth A](+)-alpha-Pinene
C10 H16
GRWFGVWFFZKLTI-RKDXNWHRSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
TMH Binding MOAD:  4I91 Kd: 220 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.183 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 77.059α = 90
b = 77.059β = 90
c = 201.847γ = 120
Software Package:
Software NamePurpose
Blu-Icedata collection
PHASERphasing
REFMACrefinement
XDSdata 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: 2013-07-03
    Type: Initial release
  • Version 1.1: 2013-08-28
    Changes: Database references
  • Version 1.2: 2014-12-31
    Changes: Non-polymer description
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Atomic model, Data collection, Database references, Derived calculations, Non-polymer description, Structure summary
  • Version 2.1: 2023-09-20
    Changes: Data collection, Database references, Refinement description, Structure summary