X-ray structure of calcineurin inhibited by the immunophilin-immunosuppressant FKBP12-FK506 complex

Griffith, Jeffrey K.; Kim, Joseph L.; Kim, Eunice E; Sintchak, Michael D.; Thomson, John A.; Fitzgibbon, Matthew J.; Fleming, Mark; Caron, Paul L.; Hsiao, Kathy; Navia, Manuel A.

doi:10.1016/0092-8674(95)90439-5

Cited by 830 publications

(755 citation statements)

References 63 publications

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“…Very similar to CsA, also the effective physiological target of FK506 is not FKBP alone but a complex of the FKBP-bound FK506 and the phosphatase calcineurin [24]. Similar to the situation with CsA-CypA, the FK506-FKBP complex inhibits calcineurin by obstructing the active site of the phosphatase as shown in the crystal structure of the ternary complex published by scientists from Vertex [29].…”

Section: Fk506 (Tacrolimus)mentioning

confidence: 94%

Stabilization of protein–protein interactions by small molecules

Giordanetto¹,

Schäfer

Ottmann

2014

Drug Discovery Today

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Section: Fk506 (Tacrolimus)mentioning

confidence: 94%

Stabilization of protein–protein interactions by small molecules

Giordanetto¹,

Schäfer

Ottmann

2014

Drug Discovery Today

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“…The X-ray crystal structure of calcineurin, complexed with FKBP and FK506 but not calmodulin, was solved very recently at a resolution of 2.5 A [9]. It is interesting to compare our NMR observations with this X-ray structure.…”

Section: Discussionmentioning

confidence: 93%

“…In CHAPS-CnB, the N-terminal residues (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), the C-terminal residues (158-169) and the linker connecting the two domains (residues 81-86) show increased mobility as judged by narrow, intense ~SN-~H cross-peaks and relatively fast amide proton exchange [15,27]. In CnB-P2465, only the N-terminus and the last three C-terminal residues retain this increased mobility.…”

Section: Resultsmentioning

confidence: 99%

“…This peptide fragment is one residue longer than the minimal peptide previously implicated in CnA binding [14] and 7 residues shorter at its C-terminus than the CnA sequence found to contact CnB in the crystal structure [9]. However, out of a large array of peptide fragments (H. Ren and C.B.…”

Section: Introductionmentioning

confidence: 85%

“…However, subsequent mutagenesis experiments showed that certain CnA mutants were capable of binding CnB, but these mutant complexes would not bind to immunophilin-drug complexes, casting some doubts on an exclusive CnB/immunophilin-drug interaction [8]. The structure of the complex between CnA, CnB, FKBP and FK506 has been solved very recently by X-ray crystallography and confirms that the FKBP-FK506 complex includes direct interactions with both the CnA and CnB subunits [9].…”

Section: Introductionmentioning

confidence: 99%

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NMR identification of calcineurin B residues affected by binding of a calcineurin A peptide

et al. 1995

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Triple resonance 3D NMR methods have been used to study the interaction between caicineurin B and a peptide fragment of calcineurin A for which it has high affinity (K D ~4 × 10 -7 M). Although calcineurin B aggregates at NMR concentrations of ~1 mM, in the presence of a target peptide fragment of caicineurin A it becomes monomeric and yields NMR spectra that are very similar to those reported previously for calcineurin B solubilized by the zwitterionic detergent CHAPS. Changes in chemical shifts between CHAPS-and peptide-solubilized calcineurin B are small which is indicative of no differences in secondary structure. Residues most affected by binding to target peptide are found primarily on the hydrophobic faces of the four helices, present in each of the two globular domains in calcineurin B, and in the loops connecting helices II and III, IV and V, and possibly in the C-terminal 12 residues, which also exhibit a change in mobility.

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Mean field analysis of FKBP12 complexes with FK506 and rapamycin: Implications for a role of crystallographic water molecules in molecular recognition and specificity

Rejto¹,

Verkhivker²

1997

Proteins

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Mean field analysis of FKBP12 complexes with FK506 and rapamycin has been performed by using structures obtained from molecular docking simulations on a simple, yet robust molecular recognition energy landscape. When crystallographic water molecules are included in the simulations as an extension of the FKBP12 protein surface, there is an appreciable stability gap between the energy of the native FKBP12-FK506 complex and energies of conformations with the "native-like" binding mode. By contrast, the energy spectrum of the FKBP12-rapamycin complex is dense regardless of the presence of the water molecules. The stability gap in the FKBP12-FK506 system is determined by two critical water molecules from the effector region that participate in a network of specific hydrogen bond interactions. This interaction pattern protects the integrity and precision of the composite ligand-protein effector surface in the binary FKBP12-FK506 complex and is preserved in the crystal structure of the FKBP12-FK506-calcineurin ternary complex. These features of the binding energy landscapes provide useful insights into specific and nonspecific aspects of FK506 and rapamycin recognition.

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X-ray structure of calcineurin inhibited by the immunophilin-immunosuppressant FKBP12-FK506 complex

Cited by 830 publications

References 63 publications

Stabilization of protein–protein interactions by small molecules

Stabilization of protein–protein interactions by small molecules

NMR identification of calcineurin B residues affected by binding of a calcineurin A peptide

Mean field analysis of FKBP12 complexes with FK506 and rapamycin: Implications for a role of crystallographic water molecules in molecular recognition and specificity

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