The 3D structure of a cyclosporin analogue in water is nearly identical to the cyclophilin‐bound cyclosporin conformation

Wenger, Roland M.; France, Julien; Bovermann, Günter; Walliser, Louis; Widmer, Armin; Widmer, Hans

doi:10.1016/0014-5793(94)80149-5

Cited by 78 publications

(70 citation statements)

References 33 publications

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“…The basic assumption is that the bioactive conformer is very likely one of those present in the solution conformational ensemble, even though it might not be the most populated conformer [51,52] . This had been found to be the case in a number of examples such as the binding of geldanamycin and radicicol to Hsp90 [52] or the binding of a water soluble analogue of the flexible cyclic peptide cyclosporine A to cyclophilin [53,54] . So, it came as no surprise that, in the case of taxol, one of the conformers found in free solution is the best candidate for binding to b -tubulin [25] .…”

Section: Determination Of Solution Conformations Of the Uncomplexed Lmentioning

confidence: 95%

The Tubulin Binding Mode of MT Stabilizing and Destabilizing Agents Studied by NMR

Sánchez-Pedregal

Griesinger

2008

Topics in Current Chemistry

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Tubulin is a fascinating molecule that forms the cytoskeleton of the cells and plays an important role in cell division and trafficking of molecules. It polymerizes and depolymerizes in order to fulfill this biological function. This function can be modulated by small molecules that interfere with the polymerization or the depolymerization. In this article, the structural basis of this behavior is reviewed with special attention to the contribution of NMR spectroscopy. Complex structures of small molecules that bind to tubulin and microtubules will be discussed. Many of them have been determined using NMR spectroscopy, which proves to be an important method in tubulin research.

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Section: Determination Of Solution Conformations Of the Uncomplexed Lmentioning

confidence: 95%

The Tubulin Binding Mode of MT Stabilizing and Destabilizing Agents Studied by NMR

Sánchez-Pedregal

Griesinger

2008

Topics in Current Chemistry

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“…32, and for more details see Ref. 33). MeVal-4-CS was obtained by total synthesis using the Merrifield technique (to be published elsewhere).…”

Section: Methodsmentioning

confidence: 99%

Interactions of Cyclophilin with the Mitochondrial Inner Membrane and Regulation of the Permeability Transition Pore, a Cyclosporin A-sensitive Channel

Nicolli

Basso

Petronilli

et al. 1996

Journal of Biological Chemistry

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453

316

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Mammalian mitochondria possess an inner membrane channel, the permeability transition pore (MTP), which can be inhibited by nanomolar concentrations of cyclosporin (CS) A. The molecular basis for MTP inhibition by CSA remains unclear. Mitochondria also possess a matrix cyclophilin (CyP) with a unique N-terminal sequence (CyP-M). To test the hypothesis that it interacts with the MTP, we have studied the interactions of CyP-M with rat liver mitochondria by Western blotting with a specific antibody against its unique N terminus. Although sonication in isotonic sucrose at pH 7.4 releases a large proportion of CyP-M, a sizeable CyP-M fraction sediments with submitochondrial particles at 150,000 ؋ g. We show that the interactions of this CyP-M pool with submitochondrial particles are disrupted (i) by the addition of CSA, which inhibits the pore, but not of CSH, which does not, and (ii) by acidic pH condition, which also leads to selective inhibition of the MTP; furthermore, we show that the effect of acidic pH on CyP-M binding is prevented by diethylpyrocarbonate, which fully prevents the inhibitory effect of H ؉ on the MTP (Nicolli, A., Petronilli, V., and Bernardi, P. (1993) Biochemistry 32, 4461-4465). These data suggest that CyP-M binding is involved in opening of the MTP and that pore inhibition by CSA and protons may be due to unbinding of CyP-M from its putative binding site on the MTP. A role for CyP-M in MTP regulation is also supported by a study with a series of CSA derivatives with graded affinity for CyP. We show that with each derivative the potency at inhibition of the peptidylprolyl cis-transisomerase activity of CyP-M purified to homogeneity is similar to that displayed at inhibition of MTP opening, relative to that displayed by CSA. Decreased binding to CyP-M (but not CyP-A) and decreased efficiency at MTP inhibition is obtained by substitutions in position 8 while a 4-substituted, nonimmunosuppressive derivative is as effective as the native CSA molecule, indicating that calcineurin is not involved in MTP inhibition by CSA.

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“…Sar 3 is an N-methylglycine and involved in a ␤-IIЈ turn conformation (41) in the structure of uncomplexed CsA. 4) By using CD spectroscopy and time-dependent Cyp18 inhibition assays, 2 we were able to demonstrate that the substitution on the Sar 3 residue has a remarkable influence on the conformation of CsA (16,43), resulting in a significantly impaired ␤-IIЈ turn signal as well as dramatically increased Cyp18 binding kinetics.…”

Section: Discussionmentioning

confidence: 91%

“…Sar 3 had been chosen for modification because of its importance in the control of the CsA conformation (16 CsA suppressed T cell proliferation and cytokine production, and blocked the activation of NFAT.…”

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confidence: 99%

Substitution in Position 3 of Cyclosporin A Abolishes the Cyclophilin-mediated Gain-of-function Mechanism but Not Immunosuppression

Baumgrass

Zhang

Erdmann

et al. 2004

Journal of Biological Chemistry

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Both immunosuppressive drugs cyclosporin A (CsA) 1 and tacrolimus (FK506) are believed to inhibit antigen-specific activation of lymphocytes by blocking T cell receptor (TCR) signaling cascades through targeting the Ca 2ϩ /calmodulindependent Ser/Thr phosphatase calcineurin (1, 2), which represents a specific bottleneck of antigen-receptor signaling. The drugs alone do not inhibit the enzymatic activity of calcineurin. CsA and FK506 bind to and inhibit calcineurin only after interaction with their respective peptidyl-prolyl cis/trans isomerases (PPIases) (EC 5.2.1.8), cyclophilins (Cyps), and FK506-binding proteins (FKBPs) through a gain-of-function mechanism. Therefore, these particular PPIases were also termed immunophilins. Among the many known human PPIases, the most abundant cytosolic members cyclophilin 18 (Cyp18) and FKBP12 were found as major receptor proteins for CsA and FK506, respectively (2, 3). Based on the structures of FKBP12-FK506-calcineurin (4, 5) and Cyp18-CsA-calcineurin complexes (6, 7), it is proposed that the inhibition of calcineurin results from blockage of access for protein substrates to the active site by the drug-immunophilin complexes, but does not involve a direct contact to the catalytic center of the protein phosphatase.

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The 3D structure of a cyclosporin analogue in water is nearly identical to the cyclophilin‐bound cyclosporin conformation

Cited by 78 publications

References 33 publications

The Tubulin Binding Mode of MT Stabilizing and Destabilizing Agents Studied by NMR

The Tubulin Binding Mode of MT Stabilizing and Destabilizing Agents Studied by NMR

Interactions of Cyclophilin with the Mitochondrial Inner Membrane and Regulation of the Permeability Transition Pore, a Cyclosporin A-sensitive Channel

Substitution in Position 3 of Cyclosporin A Abolishes the Cyclophilin-mediated Gain-of-function Mechanism but Not Immunosuppression

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