1F40

SOLUTION STRUCTURE OF FKBP12 COMPLEXED WITH GPI-1046, A NEUROTROPHIC LIGAND


Experimental Data Snapshot

  • Method: SOLUTION NMR
  • Conformers Calculated: 50 
  • Conformers Submitted: 10 
  • Selection Criteria: structures with acceptable covalent geometry,structures with favorable non-bond energy,structures with the least restraint violations 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Solution structure of a neurotrophic ligand bound to FKBP12 and its effects on protein dynamics.

Sich, C.Improta, S.Cowley, D.J.Guenet, C.Merly, J.P.Teufel, M.Saudek, V.

(2000) Eur J Biochem 267: 5342-5354

  • DOI: https://doi.org/10.1046/j.1432-1327.2000.01551.x
  • Primary Citation of Related Structures:  
    1F40

  • PubMed Abstract: 

    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.


  • Organizational Affiliation

    Department of Structural Biology and Cheminformatics, Department of Biotechnology, Sanofi-Synthelabo, Strasbourg, France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
FK506 BINDING PROTEIN (FKBP12)107Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P62942 (Homo sapiens)
Explore P62942 
Go to UniProtKB:  P62942
PHAROS:  P62942
GTEx:  ENSG00000088832 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP62942
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
GPI
Query on GPI

Download Ideal Coordinates CCD File 
B [auth A](2S)-[3-PYRIDYL-1-PROPYL]-1-[3,3-DIMETHYL-1,2-DIOXOPENTYL]-2-PYRROLIDINECARBOXYLATE
C20 H28 N2 O4
OQAHHWOPVDDWHD-INIZCTEOSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
GPI BindingDB:  1F40 Ki: min: 1.00e-2, max: 7.5 (nM) from 3 assay(s)
IC50: 1240 (nM) from 1 assay(s)
PDBBind:  1F40 Kd: 1000 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: SOLUTION NMR
  • Conformers Calculated: 50 
  • Conformers Submitted: 10 
  • Selection Criteria: structures with acceptable covalent geometry,structures with favorable non-bond energy,structures with the least restraint violations 

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2000-11-08
    Type: Initial release
  • Version 1.1: 2008-04-27
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2022-02-16
    Changes: Data collection, Database references, Derived calculations