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PDBsum entry 4i4h

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protein ligands links
Oxidoreductase/oxidoreductase inhibitor PDB id
4i4h
Jmol
Contents
Protein chain
457 a.a.
Ligands
HEM-Z9Z
PDB id:
4i4h
Name: Oxidoreductase/oxidoreductase inhibitor
Title: Crystal structure of cyp3a4 ligated to pyridine-substituted desoxyritonavir
Structure: Cytochrome p450 3a4. Chain: a. Synonym: 1,8-cineole 2-exo-monooxygenase, albendazole monoo albendazole sulfoxidase, cypiiia3, cypiiia4, cytochrome p45 cytochrome p450 hlp, cytochrome p450 nf-25, cytochrome p450 nifedipine oxidase, quinine 3-monooxygenase, taurochenodeox 6-alpha-hydroxylase. Ec: 1.14.13.-, 1.14.13.157, 1.14.13.32, 1.14.13.67, 1.14.13 engineered: yes.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: cyp3a4, cyp3a3. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Resolution:
2.90Å     R-factor:   0.198     R-free:   0.269
Authors: I.F.Sevrioukova,T.L.Poulos
Key ref: I.F.Sevrioukova and T.L.Poulos (2013). Pyridine-substituted desoxyritonavir is a more potent inhibitor of cytochrome P450 3A4 than ritonavir. J Med Chem, 56, 3733-3741. PubMed id: 23586711 DOI: 10.1021/jm400288z
Date:
27-Nov-12     Release date:   24-Apr-13    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P08684  (CP3A4_HUMAN) -  Cytochrome P450 3A4
Seq:
Struc:
503 a.a.
457 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 1: E.C.1.14.13.157  - 1,8-cineole 2-exo-monooxygenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: 1,8-cineole + NADPH + O2 = 2-exo-hydroxy-1,8-cineole + NADP+ + H2O
1,8-cineole
+ NADPH
+ O(2)
= 2-exo-hydroxy-1,8-cineole
+ NADP(+)
+ H(2)O
      Cofactor: Heme-thiolate
   Enzyme class 2: E.C.1.14.13.32  - Albendazole monooxygenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Albendazole + NADPH + O2 = albendazole S-oxide + NADP+ + H2O
Albendazole
+ NADPH
+ O(2)
= albendazole S-oxide
+ NADP(+)
+ H(2)O
      Cofactor: FAD
FAD
   Enzyme class 3: E.C.1.14.13.67  - Quinine 3-monooxygenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Quinine + NADPH + O2 = 3-hydroxyquinine + NADP+ + H2O
Quinine
Bound ligand (Het Group name = HEM)
matches with 42.55% similarity
+ NADPH
+ O(2)
= 3-hydroxyquinine
+ NADP(+)
+ H(2)O
      Cofactor: Heme-thiolate
   Enzyme class 4: E.C.1.14.13.97  - Taurochenodeoxycholate 6-alpha-hydroxylase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction:
1. Taurochenodeoxycholate + NADPH + O2 = taurohyocholate + NADP+ + H2O
2. Lithocholate + NADPH + O2 = hyodeoxycholate + NADP+ + H2O
Taurochenodeoxycholate
+ NADPH
+ O(2)
=
taurohyocholate
Bound ligand (Het Group name = HEM)
matches with 52.94% similarity
+ NADP(+)
+ H(2)O
Lithocholate
Bound ligand (Het Group name = HEM)
matches with 59.09% similarity
+ NADPH
+ O(2)
= hyodeoxycholate
+ NADP(+)
+ H(2)O
      Cofactor: Heme-thiolate
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   7 terms 
  Biological process     lipid metabolic process   16 terms 
  Biochemical function     oxidoreductase activity     18 terms  

 

 
    reference    
 
 
DOI no: 10.1021/jm400288z J Med Chem 56:3733-3741 (2013)
PubMed id: 23586711  
 
 
Pyridine-substituted desoxyritonavir is a more potent inhibitor of cytochrome P450 3A4 than ritonavir.
I.F.Sevrioukova, T.L.Poulos.
 
  ABSTRACT  
 
Utilization of the cytochrome P450 3A4 (CYP3A4) inhibitor ritonavir as a pharmacoenhancer for anti-HIV drugs revolutionized the treatment of HIV infection. However, owing to ritonavir-related complications, there is a need for development of new CYP3A4 inhibitors with improved pharmacochemical properties, which requires a full understanding of the CYP3A4 inactivation mechanisms and the unraveling of possible inhibitor binding modes. We investigated the mechanism of CYP3A4 interaction with three desoxyritonavir analogues, containing the heme-ligating imidazole, oxazole, or pyridine group instead of the thiazole moiety (compounds 1, 2, and 3, respectively). Our data show that compound 3 is superior to ritonavir in terms of binding affinity and inhibitory potency owing to greater flexibility and the ability to adopt a conformation that minimizes steric clashing and optimizes protein-ligand interactions. Additionally, Ser119 was identified as a key residue assisting binding of ritonavir-like inhibitors, which emphasizes the importance of polar interactions in the CYP3A4-ligand association.