title: The X-ray structure of (MeBm2t)1-cyclosporin complexed with cyclophilin A provides an explanation for its anomalously high immunosuppressive activity.
abstract: For most of the cyclosporin A (CsA) analogs, there is generally a good correlation between cyclophilin binding and immunosuppression. However, this relationship does not seem to hold for 4-[(E)-2-butenyl]-4,4,N-trimethyl-L-threonine1 (MeBm2t)1-CsA. Its affinity for cyclophilin was reported to be approximately 1% that of CsA and its immunosuppressive activity in vitro was shown to be approximately 30% that of CsA. We report here the crystal structure of a complex between recombinant human cyclophilin A (CypA) and (MeBm2t)1-CsA which has been determined by X-ray crystallography at 2.2 A resolution and refined to an R-factor of 16.3%. (MeBm2t)1-CsA shows a similar bound conformation and network of interactions to CypA as CsA. The measured lower affinity for CypA cannot therefore be explained by a different mode of binding. We propose that the poor affinity to CypA could be accounted for by the existence of an equilibrium in aqueous solution between a 'cyclophilin bound conformation' and a 'non-binding conformation' of (MeBm2t)1-CsA. The relatively high immunosuppressive activity is suggested to result from slight conformational differences observed in the effector domain.
authors.affiliation: Sandoz AG, Basle, Switzerland.
authors.forename: V
authors.initials: V
authors.lastname: Mikol
authors.forename: J
authors.initials: J
authors.lastname: Kallen
authors.forename: M D
authors.initials: MD
authors.lastname: Walkinshaw
mesh_terms: D000591:Amino Acid Isomerases / Q000378:metabolism*; D000595:Amino Acid Sequence; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism*; D003460:Crystallization; D018360:Crystallography, X-Ray; D003524:Cyclosporins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007165:Immunosuppression Therapy; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D019696:Peptidylprolyl Isomerase; D014867:Water / Q000737:chemistry
chemical_list: D002352:Carrier Proteins; D003524:Cyclosporins; D014867:Water; C089102:cyclosporin A, 4-(2-butenyl)-4,4,N-trimethylthreonine(1)-; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase