1nmk
From Proteopedia
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| - | [[Image:1nmk.jpg|left|200px]] | + | [[Image:1nmk.jpg|left|200px]] |
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| - | '''The Sanglifehrin-Cyclophilin Interaction: Degradation Work, Synthetic Macrocyclic Analogues, X-ray Crystal Structure and Binding Data''' | + | {{Structure |
| + | |PDB= 1nmk |SIZE=350|CAPTION= <scene name='initialview01'>1nmk</scene>, resolution 2.10Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=SFM:(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'>SFM</scene> | ||
| + | |ACTIVITY= [http://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.2.1.8 5.2.1.8] | ||
| + | |GENE= PPIA OR CYPA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | }} | ||
| + | |||
| + | '''The Sanglifehrin-Cyclophilin Interaction: Degradation Work, Synthetic Macrocyclic Analogues, X-ray Crystal Structure and Binding Data''' | ||
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==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1NMK is a [ | + | 1NMK is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1NMK OCA]. |
==Reference== | ==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:[http:// | + | 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:[http://www.ncbi.nlm.nih.gov/pubmed/12656618 12656618] |
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Peptidylprolyl isomerase]] | [[Category: Peptidylprolyl isomerase]] | ||
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[[Category: rotamase]] | [[Category: rotamase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 12:58:51 2008'' |
Revision as of 10:58, 20 March 2008
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| , resolution 2.10Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | |||||||
| Gene: | PPIA OR CYPA (Homo sapiens) | ||||||
| Activity: | Peptidylprolyl isomerase, with EC number 5.2.1.8 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
The Sanglifehrin-Cyclophilin Interaction: Degradation Work, Synthetic Macrocyclic Analogues, X-ray Crystal Structure and Binding Data
Overview
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.
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
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