Atomic View of Aqueous Cyclosporine A: Unpacking a Decades-Old Mystery.
J Am Chem Soc
; 144(28): 12602-12607, 2022 07 20.
Article
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| MEDLINE
| ID: mdl-35786958
ABSTRACT
An atomic view of a main aqueous conformation of cyclosporine A (CycA), an important 11-amino-acid macrocyclic immunosuppressant, is reported. For decades, it has been a grand challenge to determine the conformation of free CycA in an aqueous-like solution given its poor water solubility. Using a combination of X-ray and single-crystal neutron diffraction, we unambiguously resolve a unique conformer (A1) with a novel cis-amide between residues 11 and 1 and two water ligands that stabilize hydrogen bond networks. NMR spectroscopy and titration experiments indicate that the novel conformer is as abundant as the closed conformer in 90/10 (v/v) methanol/water and is the main conformer at 10/90 methanol/water. Five other conformers were also detected in 90/10 methanol/water, one in slow exchange with A1, another one in slow exchange with the closed form and three minor ones, one of which contains two cis amides Abu2-Sar3 and MeBmt1-MeVal11. These conformers help better understand the wide spectrum of membrane permeability observed for CycA analogues and, to some extent, the binding of CycA to protein targets.
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1
Banco de datos:
MEDLINE
Asunto principal:
Ciclosporina
/
Metanol
Idioma:
En
Año:
2022
Tipo del documento:
Article