From Proteopedia
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| | {{STRUCTURE_1nmk| PDB=1nmk | SCENE= }} | | {{STRUCTURE_1nmk| PDB=1nmk | SCENE= }} |
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| - | '''The Sanglifehrin-Cyclophilin Interaction: Degradation Work, Synthetic Macrocyclic Analogues, X-ray Crystal Structure and Binding Data'''
| + | ===The Sanglifehrin-Cyclophilin Interaction: Degradation Work, Synthetic Macrocyclic Analogues, X-ray Crystal Structure and Binding Data=== |
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| - | ==Overview==
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| - | 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.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_12656618}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 12656618 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_12656618}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Isomerase]] | | [[Category: Isomerase]] |
| | [[Category: Rotamase]] | | [[Category: Rotamase]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 02:42:43 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 03:57:43 2008'' |
Revision as of 00:57, 29 July 2008
Template:STRUCTURE 1nmk
The Sanglifehrin-Cyclophilin Interaction: Degradation Work, Synthetic Macrocyclic Analogues, X-ray Crystal Structure and Binding Data
Template:ABSTRACT PUBMED 12656618
About this Structure
1NMK is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Sanglifehrin-cyclophilin interaction: degradation work, synthetic macrocyclic analogues, X-ray crystal structure, and binding data., Sedrani R, Kallen J, Martin Cabrejas LM, Papageorgiou CD, Senia F, Rohrbach S, Wagner D, Thai B, Jutzi Eme AM, France J, Oberer L, Rihs G, Zenke G, Wagner J, J Am Chem Soc. 2003 Apr 2;125(13):3849-59. PMID:12656618
Page seeded by OCA on Tue Jul 29 03:57:43 2008
