6UX0 | pdb_00006ux0

Isavuconazole bound complex of Acanthamoeba castellanii CYP51


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.93 ?
  • R-Value Free: 
    0.308 (Depositor) 
  • R-Value Work: 
    0.213 (Depositor) 
  • R-Value Observed: 
    0.218 (Depositor) 

Starting Model: experimental
View more details

wwPDB Validation   3D Report Full Report

Currently 6UX0 does not have a validation slider image.


This is version 1.3 of the entry. See complete history


Literature

Domain-Swap Dimerization of Acanthamoeba castellanii CYP51 and a Unique Mechanism of Inactivation by Isavuconazole.

Sharma, V.Shing, B.Hernandez-Alvarez, L.Debnath, A.Podust, L.M.

(2020) Mol Pharmacol 98: 770-780

  • DOI: https://doi.org/10.1124/molpharm.120.000092
  • Primary Citation of Related Structures:  
    6Q2C, 6UW2, 6UX0

  • PubMed Abstract: 

    Cytochromes P450 (P450, CYP) metabolize a wide variety of endogenous and exogenous lipophilic molecules, including most drugs. Sterol 14 ¦Á -demethylase (CYP51) is a target for antifungal drugs known as conazoles. Using X-ray crystallography, we have discovered a domain-swap homodimerization mode in CYP51 from a human pathogen, Acanthamoeba castellanii CYP51 (AcCYP51). Recombinant AcCYP51 with a truncated transmembrane helix was purified as a heterogeneous mixture corresponding to the dimer and monomer units. Spectral analyses of these two populations have shown that the CO-bound ferrous form of the dimeric protein absorbed at 448 nm (catalytically competent form), whereas the monomeric form absorbed at 420 nm (catalytically incompetent form). AcCYP51 dimerized head-to-head via N-termini swapping, resulting in formation of a nonplanar protein-protein interface exceeding 2000 ? 2 with a total solvation energy gain of -35.4 kcal/mol. In the dimer, the protomers faced each other through the F and G ¦Á -helices, thus blocking the substrate access channel. In the presence of the drugs clotrimazole and isavuconazole, the AcCYP51 drug complexes crystallized as monomers. Although clotrimazole-bound AcCYP51 adopted a typical CYP monomer structure, isavuconazole-bound AcCYP51 failed to refold 74 N-terminal residues. The failure of AcCYP51 to fully refold upon inhibitor binding in vivo would cause an irreversible loss of a structurally aberrant enzyme through proteolytic degradation. This assumption explains the superior potency of isavuconazole against A. castellanii The dimerization mode observed in this work is compatible with membrane association and may be relevant to other members of the CYP family of biologic, medical, and pharmacological importance. SIGNIFICANCE STATEMENT: We investigated the mechanism of action of antifungal drugs in the human pathogen Acanthamoeba castellanii . We discovered that the enzyme target [ Acanthamoeba castellanii sterol 14 ¦Á -demethylase (AcCYP51)] formed a dimer via an N-termini swap, whereas drug-bound AcCYP51 was monomeric. In the AcCYP51-isavuconazole complex, the protein target failed to refold 74 N-terminal residues, suggesting a fundamentally different mechanism of AcCYP51 inactivation than only blocking the active site. Proteolytic degradation of a structurally aberrant enzyme would explain the superior potency of isavuconazole against A. castellanii .


  • Organizational Affiliation

    Skaggs School of Pharmacy and Pharmaceutical Sciences, Center for Discovery and Innovation in Parasitic Diseases, University of California San Diego, La Jolla, California (V.S., B.S., L.H.-A., A.D., L.M.P.) and Departamento de F¨ªsica, Instituto de Bioci¨ºncias, Letras e Ci¨ºncias Exatas, Universidade Estadual Paulista Julio de Mesquita Filho, S?o Jos¨¦ do Rio Preto, S?o Paulo, Brazil (L.H.-A.).


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Obtusifoliol 14alphademethylase
A, B, C, D, E
A, B, C, D, E, F
460Acanthamoeba castellanii str. NeffMutation(s): 0 
Gene Names: ACA1_372720
Membrane Entity: Yes 
UniProt
Find proteins for L8GJB3 (Acanthamoeba castellanii (strain ATCC 30010 / Neff))
Explore L8GJB3 
Go to UniProtKB:  L8GJB3
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupL8GJB3
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HEM
Query on HEM

Download Ideal Coordinates CCD File 
G [auth A]
I [auth B]
L [auth C]
N [auth D]
P [auth E]
G [auth A],
I [auth B],
L [auth C],
N [auth D],
P [auth E],
R [auth F]
PROTOPORPHYRIN IX CONTAINING FE
C34 H32 Fe N4 O4
KABFMIBPWCXCRK-RGGAHWMASA-L
QKM (Subject of Investigation/LOI)
Query on QKM

Download Ideal Coordinates CCD File 
H [auth A]
J [auth B]
M [auth C]
O [auth D]
Q [auth E]
H [auth A],
J [auth B],
M [auth C],
O [auth D],
Q [auth E],
S [auth F]
4-{2-[(2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl]-1,3-thiazol-4-yl}benzonitrile
C22 H17 F2 N5 O S
DDFOUSQFMYRUQK-RCDICMHDSA-N
FE
Query on FE

Download Ideal Coordinates CCD File 
K [auth B],
T [auth F]
FE (III) ION
Fe
VTLYFUHAOXGGBS-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.93 ?
  • R-Value Free:  0.308 (Depositor) 
  • R-Value Work:  0.213 (Depositor) 
  • R-Value Observed: 0.218 (Depositor) 
Space Group: P 1
Unit Cell:
Length ( ? )Angle ( ? )
a = 99.45¦Á = 92.61
b = 99.06¦Â = 96.2
c = 108.71¦Ã = 120.09
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XDSdata scaling
MOLREPphasing

Structure Validation

View Full Validation Report

Currently 6UX0 does not have a validation slider image.



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2020-10-21
    Type: Initial release
  • Version 1.1: 2020-12-02
    Changes: Database references
  • Version 1.2: 2022-07-06
    Changes: Database references, Derived calculations
  • Version 1.3: 2023-10-11
    Changes: Data collection, Refinement description
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