X-ray structure of alisporivir in complex with cyclophilin A at 1.5 Å resolution - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Acta crystallographica Section F : Structural biology communications [2014-...] Année : 2018

X-ray structure of alisporivir in complex with cyclophilin A at 1.5 Å resolution

Résumé

Alisporivir (ALV) is an 11-amino-acid hydrophobic cyclic peptide with N-methyl-d-alanine and N-ethyl-l-valine (NEV) residues at positions 3 and 4, respectively. ALV is a non-immunosuppressive cyclosporin A (CsA) derivative. This inhibitor targets cyclophilins (Cyps), a family of proteins with peptidyl-prolyl cis/trans isomerase enzymatic activity. Cyps act as protein chaperones and are involved in numerous cellular functions. Moreover, Cyps have been shown to be an essential cofactor for the replication of many viruses, including Hepatitis C virus and Human immunodeficiency virus, and have also been shown to be involved in mitochondrial diseases. For these reasons, cyclophilins represent an attractive drug target. The structure of ALV in complex with cyclophilin A (CypA), the most abundant Cyp in humans, has been determined at 1.5 A ˚ resolution. This first structure of the CypA-ALV complex shows that the binding of ALV is highly similar to that of CsA. The high resolution allowed the unambiguous determination of the conformations of residues 3 and 4 in ALV when bound to its target. In particular, the side-chain conformation of NEV4 precludes the interaction of the CypA-ALV complex with calcineurin, a cellular protein phosphatase involved in the immune response, which explains the non-immunosuppressive property of ALV. This study provides detailed molecular insights into the CypA-ALV interaction.

Dates et versions

hal-01925054 , version 1 (16-11-2018)

Identifiants

Citer

Marie Dujardin, Julie Bouckaert, Prakash Rucktooa, Xavier Hanoulle. X-ray structure of alisporivir in complex with cyclophilin A at 1.5 Å resolution. Acta crystallographica Section F : Structural biology communications [2014-..], 2018, 74 (9), pp.583 - 592. ⟨10.1107/S2053230X18010415⟩. ⟨hal-01925054⟩

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