7LAD

Clobetasol propionate bound to CYP3A5


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.65 Å
  • R-Value Free: 0.278 
  • R-Value Work: 0.250 
  • R-Value Observed: 0.251 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Unraveling the Structural Basis of Selective Inhibition of Human Cytochrome P450 3A5.

Wang, J.Buchman, C.D.Seetharaman, J.Miller, D.J.Huber, A.D.Wu, J.Chai, S.C.Garcia-Maldonado, E.Wright, W.C.Chenge, J.Chen, T.

(2021) J Am Chem Soc 143: 18467-18480

  • DOI: 10.1021/jacs.1c07066
  • Primary Citation of Related Structures:  
    7LAD

  • PubMed Abstract: 
  • The human cytochrome P450 (CYP) CYP3A4 and CYP3A5 enzymes metabolize more than one-half of marketed drugs. They share high structural and substrate similarity and are often studied together as CYP3A4/5. However, CYP3A5 preferentially metabolizes several clinically prescribed drugs, such as tacrolimus ...

    The human cytochrome P450 (CYP) CYP3A4 and CYP3A5 enzymes metabolize more than one-half of marketed drugs. They share high structural and substrate similarity and are often studied together as CYP3A4/5. However, CYP3A5 preferentially metabolizes several clinically prescribed drugs, such as tacrolimus. Genetic polymorphism in CYP3A5 makes race-based dosing adjustment of tacrolimus necessary to minimize acute rejection after organ transplantation. Moreover, the differential tissue distribution and expression levels of CYP3A4 and CYP3A5 can aggravate toxicity during treatment. Therefore, selective inhibitors of CYP3A5 are needed to distinguish the role of CYP3A5 from that of CYP3A4 and serve as starting points for potential therapeutic development. To this end, we report the crystal structure of CYP3A5 in complex with a previously reported selective inhibitor, clobetasol propionate (CBZ). This is the first CYP3A5 structure with a type I inhibitor, which along with the previously reported substrate-free and type II inhibitor-bound structures, constitute the main CYP3A5 structural modalities. Supported by structure-guided mutagenesis analyses, the CYP3A5-CBZ structure showed that a unique conformation of the F-F' loop in CYP3A5 enables selective binding of CBZ to CYP3A5. Several polar interactions, including hydrogen bonds, stabilize the position of CBZ to interact with this unique F-F' loop conformation. In addition, functional and biophysical assays using CBZ analogs highlight the importance of heme-adjacent moieties for selective CYP3A5 inhibition. Our findings can be used to guide further development of more potent and selective CYP3A5 inhibitors.


    Organizational Affiliation

    Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.



Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChainsSequence LengthOrganismDetailsImage
Cytochrome P450 3A5A481Homo sapiensMutation(s): 0 
Gene Names: CYP3A5
EC: 1.14.14.1
UniProt & NIH Common Fund Data Resources
Find proteins for P20815 (Homo sapiens)
Explore P20815 
Go to UniProtKB:  P20815
PHAROS:  P20815
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP20815
Protein Feature View
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChainsName / Formula / InChI Key2D Diagram3D Interactions
HEM (Subject of Investigation/LOI)
Query on HEM

Download Ideal Coordinates CCD File 
B [auth A]PROTOPORPHYRIN IX CONTAINING FE
C34 H32 Fe N4 O4
KABFMIBPWCXCRK-RGGAHWMASA-L
 Ligand Interaction
XRD (Subject of Investigation/LOI)
Query on XRD

Download Ideal Coordinates CCD File 
C [auth A]Clobetasol propionate
C25 H32 Cl F O5
CBGUOGMQLZIXBE-XGQKBEPLSA-N
 Ligand Interaction
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.65 Å
  • R-Value Free: 0.278 
  • R-Value Work: 0.250 
  • R-Value Observed: 0.251 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 75.404α = 90
b = 93.912β = 90
c = 138.716γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
XDSdata scaling
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesR35GM118041

Revision History  (Full details and data files)

  • Version 1.0: 2021-10-27
    Type: Initial release
  • Version 1.1: 2021-11-17
    Changes: Database references, Derived calculations, Structure summary