4RRT

Crystal structure of a human cytochrome P450 2B6 (Y226H/K262R) in complex with (+)-3-carene


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.173 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structural and Biophysical Characterization of Human Cytochromes P450 2B6 and 2A6 Bound to Volatile Hydrocarbons: Analysis and Comparison.

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

(2015) Mol Pharmacol 87: 649-659

  • DOI: https://doi.org/10.1124/mol.114.097014
  • Primary Citation of Related Structures:  
    4RQL, 4RRT, 4RUI

  • PubMed Abstract: 

    X-ray crystal structures of complexes of cytochromes CYP2B6 and CYP2A6 with the monoterpene sabinene revealed two distinct binding modes in the active sites. In CYP2B6, sabinene positioned itself with the putative oxidation site located closer to the heme iron. In contrast, sabinene was found in an alternate conformation in the more compact CYP2A6, where the larger hydrophobic side chains resulted in a significantly reduced active-site cavity. Furthermore, results from isothermal titration calorimetry indicated a much more substantial contribution of favorable enthalpy to sabinene binding to CYP2B6 as opposed to CYP2A6, consistent with the previous observations with (+)-α-pinene. Structural analysis of CYP2B6 complexes with sabinene and the structurally similar (3)-carene and comparison with previously solved structures revealed how the movement of the F206 side chain influences the volume of the binding pocket. In addition, retrospective analysis of prior structures revealed that ligands containing -Cl and -NH functional groups adopted a distinct orientation in the CYP2B active site compared with other ligands. This binding mode may reflect the formation of Cl-π or NH-π bonds with aromatic rings in the active site, which serve as important contributors to protein-ligand binding affinity and specificity. Overall, the findings from multiple techniques illustrate how drugs metabolizing CYP2B6 and CYP2A6 handle a common hydrocarbon found in the environment. The study also provides insight into the role of specific functional groups of the ligand that may influence the binding to CYP2B6.


  • Organizational Affiliation

    Department of Pharmaceutical Sciences, The University of Connecticut, Storrs, Connecticut (M.B.S., P.R.W., J.L., J.R.H.); School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea (H.-H.J.); and Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California (Q.Z., C.D.S.) manish.shah@uconn.edu.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cytochrome P450 2B6
A, B
476Homo sapiensMutation(s): 10 
Gene Names: CYP2B6
EC: 1.14.13 (PDB Primary Data), 1.14.14.1 (PDB Primary Data)
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 
C [auth A],
J [auth B]
PROTOPORPHYRIN IX CONTAINING FE
C34 H32 Fe N4 O4
KABFMIBPWCXCRK-RGGAHWMASA-L
CM5
Query on CM5

Download Ideal Coordinates CCD File 
E [auth A]
F [auth A]
G [auth A]
L [auth B]
M [auth B]
E [auth A],
F [auth A],
G [auth A],
L [auth B],
M [auth B],
N [auth B]
5-CYCLOHEXYL-1-PENTYL-BETA-D-MALTOSIDE
C23 H42 O11
RVTGFZGNOSKUDA-ZNGNCRBCSA-N
3V4
Query on 3V4

Download Ideal Coordinates CCD File 
D [auth A],
K [auth B]
(+)-3-carene
C10 H16
BQOFWKZOCNGFEC-DTWKUNHWSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
H [auth A],
I [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
3V4 Binding MOAD:  4RRT Kd: 1820 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.173 
  • Space Group: P 32
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 78.07α = 90
b = 78.07β = 90
c = 203.081γ = 120
Software Package:
Software NamePurpose
Blu-Icedata collection
PHASERphasing
REFMACrefinement
iMOSFLMdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2015-01-28 
  • Deposition Author(s): Shah, M.B.

Revision History  (Full details and data files)

  • Version 1.0: 2015-01-28
    Type: Initial release
  • Version 1.1: 2015-03-11
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations