1NMK

The Sanglifehrin-Cyclophilin Interaction: Degradation Work, Synthetic Macrocyclic Analogues, X-ray Crystal Structure and Binding Data

Summary for 1NMK

• Entry DOI: 10.2210/pdb1nmk/pdb
• Descriptor: Peptidyl-prolyl cis-trans isomerase A, (13E,15E)-(3S,6S,9R,10R,11S,12S,18S,21S)-10,12-DIHYDROXY-3-(3-HYDROXYBEN-ZYL)-18-((E)-3-HYDROXY-1-METHYLPROPENYL)-6-ISOPROPYL-11-METHYL-9-(3-OXO-BUTYL)-19-OXA-1,4,7,25-TETRAAZA-BICYCLO[19.3.1]PENTACOSA-13,15-DIENE-2,5,8,20-TETRAONE (3 entities in total)
• Functional Keywords: beta sandwich, cyclophilin-ligand complex, cyclosporin, isomerase, rotamase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P62937
• Total number of polymer chains: 2
• Total formula weight: 37554.77

Authors

Kallen, J.,Sedrani, R.,Wagner, J. (deposition date: 2003-01-10, release date: 2003-04-01, Last modification date: 2023-08-16)

Primary citation

Sedrani, R.,Kallen, J.,Cabrejas, L.M.M.,Papageorgiou, C.D.,Senia, F.,Rohrbach, S.,Wagner, D.,Thai, B.,Eme, A.-M.J.,France, J.,Oberer, L.,Rihs, G.,Zenke, G.,Wagner, J.
Sanglifehrin-Cyclophilin Interaction: Degradation Work, Synthetic Macrocyclic Analogues, X-ray Crystal Structure and Binding Data
J.Am.Chem.Soc., 125:3849-3859, 2003

PubMed Abstract: Sanglifehrin A (SFA) is a novel immunosuppressive natural product isolated from Streptomyces sp. A92-308110. SFA has a very strong affinity for cyclophilin A (IC(50) = 6.9 +/- 0.9 nM) but is structurally different from cyclosporin A (CsA) and exerts its immunosuppressive activity via a novel mechanism. SFA has a complex molecular structure consisting of a 22-membered macrocycle, bearing in position 23 a nine-carbon tether terminated by a highly substituted spirobicyclic moiety. Selective oxidative cleavage of the C(26)=C(27) exocyclic double bond affords the spirolactam containing fragment 1 and macrolide 2. The affinity of 2 for cyclophilin (IC(50) = 29 +/- 2.1 nM) is essentially identical to SFA, which indicates that the interaction between SFA and cyclophilin A is mediated exclusively by the macrocyclic portion of the molecule. This observation was confirmed by the X-ray crystal structure resolved at 2.1 A of cyclophilin A complexed to macrolide 16, a close analogue of 2. The X-ray crystal structure showed that macrolide 16 binds to the same deep hydrophobic pocket of cyclophilin A as CsA. Additional valuable details of the structure-activity relationship were obtained by two different chemical approaches: (1) degradation work on macrolide 2 or (2) synthesis of a library of macrolide analogues using the ring-closing metathesis reaction as the key step. Altogether, it appears that the complex macrocyclic fragment of SFA is a highly optimized combination of multiple functionalities including an (E,E)-diene, a short polypropionate fragment, and an unusual tripeptide unit, which together provide an extremely strong affinity for cyclophilin A.

PubMed: 12656618
DOI: 10.1021/ja021327y

Experimental method

X-RAY DIFFRACTION (2.1 Å)