Four Major Channels Detected in the Cytochrome P450 3A4: A Step toward Understanding Its Multispecificity

Lydia Benkaidali (1) , François André (2, 3, 4) , Gautier Moroy (5) , Bahoueddine Tangour , François Maurel (6) , Michel Petitjean (5)

1 LBT (UPR_9080) - Laboratoire de biochimie théorique [Paris]
2 I2BC - Institut de Biologie Intégrative de la Cellule
3 LSOD - Stress Oxydants et Détoxication
4 B3S - Département Biochimie, Biophysique et Biologie Structurale
5 MTI - Molécules Thérapeutiques in silico
6 ITODYS (UMR_7086) - Interfaces, Traitements, Organisation et Dynamique des Systèmes

We computed the network of channels of the 3A4 isoform of the cytochrome P450 (CYP) on the basis of 16 crystal structures extracted from the Protein Data Bank (PDB). The calculations were performed with version 2 of the CCCPP software that we developed for this research project. We identified the minimal cost paths (MCPs) output by CCCPP as probable ways to access to the buried active site. The algorithm of calculation of the MCPs is presented in this paper, with its original method of visualization of the channels. We found that these MCPs constitute four major channels in CYP3A4. Among the many channels proposed by Cojocaru et al. in 2007, we found that only four of them open in 3A4. We provide a refined description of these channels together with associated quantitative data.

Mots clés: membrane topology; substrate-binding; steered molecular-dynamics; products exit; possible pathway(s); multiple ligand; cytochromes P450; active site access channels; ligand access; cyp3a4; minimal cost paths; access channels; buried active-site; cavities boundaries; crystal-structure; CYP3A4

Domaines: Sciences du Vivant [q-bio]

Lydia Benkaidali, François André, Gautier Moroy, Bahoueddine Tangour, François Maurel, et al.. Four Major Channels Detected in the Cytochrome P450 3A4: A Step toward Understanding Its Multispecificity. International Journal of Molecular Sciences, 2019, 20 (4), pp.987. ⟨10.3390/ijms20040987⟩. ⟨hal-02169567⟩