Two new cyclosporin folds observed in the structures of the immunosuppressant cyclosporin G and the formyl peptide receptor antagonist cyclosporin H at ultra-high resolution.
Cyclosporins are cyclic undecapeptides of fungal origin the best known of which, CsA, is a lead clinical immunosuppressant; CsG is a potential clinical immunosuppressant differing from CsA in residue 2 (L-alpha-amino-butyric acid in CsA, L-norvaline in CsG); and CsH is an inverse formyl peptide receptor agonist, differing from CsA in the chiral inversion of MeVal-11 from L to D. Crystal structure determinations of CsG and CsH were undertaken to identify structural and surface features important for biological activity and the future design of new cyclosporin derivatives. Ultra-high resolution X-ray structures (0.80 to 0.87 A resolution) determined for two crystal forms of both CsH and CsG in the presence and absence of Mg2+ are described. A major outcome of this study is the observation that the local change in chirality between CsA and CsH is associated with a major structural transformation from open beta-sheet in CsA to a highly convoluted conformation in CsH. CsG also possesses a completely novel cloverleaf motif with no H-bonded secondary structure features in spite of the minimal chemical difference with CsA. Unlike CsA, the structures of both CsH and CsG are heavily solvated. This study therefore shows that the chemical differences between the three cyclosporins, CsA, CsG and CsH can invoke unpredictably major differences in their 3D structures. The 9-11 cis-peptide bond in CsA moves to 11-1 in CsG, influencing the overall molecular conformation, while the peptide bonds in the highly convoluted loop conformation of CsH are all trans.
Potter
Brian
B
School of Crystallography, Birkbeck College, University of London, Malet Street, London, UK WC1E 7HX.
Palmer
Rex A
RA
Withnall
Robert
R
Jenkins
Terence C
TC
Chowdhry
Babur Z
BZ
D018360:Crystallography, X-Ray; D016572:Cyclosporine / Q000737:chemistry*; D006860:Hydrogen Bonding; D007166:Immunosuppressive Agents / Q000737:chemistry; D008274:Magnesium / Q000737:chemistry; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D018000:Receptors, Peptide / Q000819:agonists; D012997:Solvents / Q000737:chemistry; D013237:Stereoisomerism
D007166:Immunosuppressive Agents; D018000:Receptors, Peptide; D012997:Solvents; C045571:cyclosporin G; D016572:Cyclosporine; C050025:cyclosporin H; D008274:Magnesium