PDBsum entry 1f40

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Isomerase PDB id
Protein chain
107 a.a. *
* Residue conservation analysis

References listed in PDB file
Key reference
Title Solution structure of a neurotrophic ligand bound to fkbp12 and its effects on protein dynamics.
Authors C.Sich, S.Improta, D.J.Cowley, C.Guenet, J.P.Merly, M.Teufel, V.Saudek.
Ref. Eur J Biochem, 2000, 267, 5342-5355. [DOI no: 10.1046/j.1432-1327.2000.01551.x]
PubMed id 10951192
The structure of a recently reported neurotrophic ligand, 3-(3-pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1, 2-dioxopentyl)-2-pyrrolidinecarboxylate, in complex with FKBP12 was determined using heteronuclear NMR spectroscopy. The inhibitor exhibits a binding mode analogous to that observed for the macrocycle FK506, used widely as an immunosuppressant, with the prolyl ring replacing the pipecolyl moiety and the amide bond in a trans conformation. However, fewer favourable protein-ligand interactions are detected in the structure of the complex, suggesting weaker binding compared with the immunosuppressant drug. Indeed, a micromolar dissociation constant was estimated from the NMR ligand titration profile, in contrast to the previously published nanomolar inhibition activity. Although the inhibitor possesses a remarkable structural simplicity with respect to FK506, 15N relaxation studies show that it induces similar effects on the protein dynamics, stabilizing the conformation of solvent-exposed residues which are important for mediating the interaction of immunophilin/ligand complexes with molecular targets and potentially for the transmission of the neurotrophic action of FKBP12 inhibitors.
Figure 1.
Fig. 1. Chemical structure of the FKBP12 ligand under investigation (1), FK506 and a compound investigated by Holt et al. (2) [1].
Figure 8.
Fig. 8. Stereoview of stick models of 10 of the lowest energy structures of 1 bound to FKBP12. Ligand atoms are colored according to the atom type. The protein is represented by its contact surface.
The above figures are reprinted by permission from the Federation of European Biochemical Societies: Eur J Biochem (2000, 267, 5342-5355) copyright 2000.
Secondary reference #1
Title Neurotrophic immunophilin ligands stimulate structural and functional recovery in neurodegenerative animal models.
Authors J.P.Steiner, G.S.Hamilton, D.T.Ross, H.L.Valentine, H.Guo, M.A.Connolly, S.Liang, C.Ramsey, J.H.Li, W.Huang, P.Howorth, R.Soni, M.Fuller, H.Sauer, A.C.Nowotnik, P.D.Suzdak.
Ref. Proc Natl Acad Sci U S A, 1997, 94, 2019-2024. [DOI no: 10.1073/pnas.94.5.2019]
PubMed id 9050897
Full text Abstract
Figure 1.
Fig. 1. GPI-1046 elicits neurite outgrowth in chicken sensory neuronal cultures. Increasing concentrations of GPI-1046 were added^ to sensory neuronal cultures, and neurite outgrowth (number of^ neurites whose length is larger than the diameter of the explant) at 48 hr posttreatment was quantitated.
Figure 2.
Fig. 2. GPI-1046 protects against loss of striatal TH and promotes regeneration of striatal dopaminergic markers in MPTP-treated mice. (A) Dose dependency of GPI-1046-mediated recovery of striatal TH innervation density in the concurrent MPTP-GPI-1046 model. Quantitative analysis of striatal TH levels was as described. At all dose levels, TH innervation density was significantly greater than MPTP/vehicle-treated cases alone (Student's t test, P < 0.001). (B) The dose-dependent recovery of TH+ labeled punctae is evident in the striata of MPTP-lesioned mice treated after an 8-day delay with s.c. GPI-1046 at 4, 10, 20, or 40 mg/kg. Quantitation of^ the post-MPTP-administered GPI-1046 in regeneration of striatal TH innervation density is depicted graphically. At all dose levels, TH innervation density was significantly greater than MPTP treated^ cases alone (Student's t test, P < 0.001).
Secondary reference #2
Title Atomic structure of fkbp-Fk506, An immunophilin-Immunosuppressant complex.
Authors G.D.Van duyne, R.F.Standaert, P.A.Karplus, S.L.Schreiber, J.Clardy.
Ref. Science, 1991, 252, 839-842. [DOI no: 10.1126/science.1709302]
PubMed id 1709302
Full text Abstract
Secondary reference #3
Title Design, Synthesis, And kinetic evaluation of high-Affinity fkbp ligands and the X-Ray structure of their complexes with fkbp12
Authors D.A.Holt, J.I.Luengo, D.S.Yamashita, H.-J.Oh, A.L.Konalian, H.-K.Yen, L.W.Rozamus, M.Brandt, M.J.Bossard, M.A.Levy, D.S.Eggleston, J.Lian.
Ref. j am chem soc, 1993, 115, 9925.
Secondary reference #4
Title 15n nmr relaxation studies of the fk506 binding protein: dynamic effects of ligand binding and implications for calcineurin recognition.
Authors J.W.Cheng, C.A.Lepre, J.M.Moore.
Ref. Biochemistry, 1994, 33, 4093-4100. [DOI no: 10.1021/bi00180a001]
PubMed id 7512379
Full text Abstract
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