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Atomic View of Aqueous Cyclosporine A: Unpacking a Decades-Old Mystery.
Limbach, Miranda N; Antevska, Aleksandra; Oluwatoba, Damilola S; Gray, Amber L H; Carroll, Xian B; Hoffmann, Christina M; Wang, Xiaoping; Voehler, Markus W; Steren, Carlos A; Do, Thanh D.
Affiliation
  • Limbach MN; Department of Chemistry, University of Tennessee, Knoxville, Tennessee 37996, United States.
  • Antevska A; Department of Chemistry, University of Tennessee, Knoxville, Tennessee 37996, United States.
  • Oluwatoba DS; Department of Chemistry, University of Tennessee, Knoxville, Tennessee 37996, United States.
  • Gray ALH; Department of Chemistry, University of Tennessee, Knoxville, Tennessee 37996, United States.
  • Carroll XB; Department of Chemistry, University of Tennessee, Knoxville, Tennessee 37996, United States.
  • Hoffmann CM; Neutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United States.
  • Wang X; Neutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United States.
  • Voehler MW; Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, United States.
  • Steren CA; Department of Chemistry, University of Tennessee, Knoxville, Tennessee 37996, United States.
  • Do TD; Department of Chemistry, University of Tennessee, Knoxville, Tennessee 37996, United States.
J Am Chem Soc ; 144(28): 12602-12607, 2022 07 20.
Article in En | MEDLINE | ID: mdl-35786958
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.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cyclosporine / Methanol Language: En Journal: J Am Chem Soc Year: 2022 Document type: Article Affiliation country: United States Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cyclosporine / Methanol Language: En Journal: J Am Chem Soc Year: 2022 Document type: Article Affiliation country: United States Country of publication: United States