X-ray structure of a cyclophilin B/cyclosporin complex: comparison with cyclophilin A and delineation of its calcineurin-binding domain.
The crystal structure of a complex between recombinant human cyclophilin B (CypB) and a cyclosporin A (CsA) analog has been determined and refined at 1.85-A resolution to a crystallographic R factor of 16.0%. The overall structures of CypB and of cyclophilin A (CypA) are similar; however, significant differences occur in two loops and at the N and C termini. The CsA-binding pocket in CypB has the same structure as in CypA and cyclosporin shows a similar bound conformation and network of interactions in both CypB and CypA complexes. The network of the water-mediated contacts is also essentially conserved. The higher potency of the CypB/CsA complex versus CypA/CsA in inhibiting the Ca(2+)- and calmodulin-dependent protein phosphatase calcineurin is discussed in terms of the structural differences between the two complexes. The three residues Arg90, Lys113, and Ala128 and the loop containing Arg158 on the surface of CypB are likely to modulate the differences in calcineurin inhibition between CypA and CypB.
Mikol
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Preclinical Research, Sandoz AG, Basel, Switzerland.
Kallen
J
J
Walkinshaw
M D
MD
D000591:Amino Acid Isomerases / Q000737:chemistry* / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D021983:Cyclophilins; D016572:Cyclosporine / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D019696:Peptidylprolyl Isomerase; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
D002148:Calmodulin-Binding Proteins; D002352:Carrier Proteins; C081786:cyclophilin B; D016572:Cyclosporine; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D000591:Amino Acid Isomerases; D021983:Cyclophilins; D019696:Peptidylprolyl Isomerase