PDBsum entry 4jfl

Isomerase

PDB id: 4jfl

Contents

Protein chain

128 a.a.

Ligands

1KY

Waters ×248

PDB id:

4jfl

Name:

Isomerase

Title:

Increasing the efficiency efficiency of ligands for the fk506-binding protein 51 by conformational control: complex of fkbp51 with 6-({(1s, 5r)-3-[2-(3,4-dimethoxyphenoxy)ethyl]-2-oxo-3,9- diazabicyclo[3.3.1]non-9-yl}sulfonyl)-1,3-benzothiazol-2(3h)-one

Structure:

Peptidyl-prolyl cis-trans isomerase fkbp5. Chain: a. Fragment: unp residues 16-140. Synonym: ppiase fkbp5, 51 kda fk506-binding protein, 51 kda fkbp, fkbp-51, 54 kda progesterone receptor-associated immunophilin, androgen-regulated protein 6, ff1 antigen, fk506-binding protein 5, fkbp-5, fkbp54, p54, hsp90-binding immunophilin, rotamase. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: aig6, fkbp5, fkbp51. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.20Å R-factor: 0.143 R-free: 0.174

Authors:

Y.Wang,A.Kirschner,A.Fabian,R.Gopalakrishnan,C.Kress,B.Hoogeland, U.Koch,C.Kozany,A.Bracher,F.Hausch

Key ref:

Y.Wang et al. (2013). Increasing the efficiency of ligands for FK506-binding protein 51 by conformational control. J Med Chem, 56, 3922-3935. PubMed id: 23647266 DOI: 10.1021/jm400087k

Date:

28-Feb-13 Release date: 28-Aug-13

Protein chain

Q13451  (FKBP5_HUMAN) -  Peptidyl-prolyl cis-trans isomerase FKBP5 from Homo sapiens

Seq: 457 a.a.

Struc: 128 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.5.2.1.8 - peptidylprolyl isomerase.
• Reaction: [protein]-peptidylproline (omega=180) = [protein]-peptidylproline (omega=0)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1021/jm400087k

J Med Chem 56:3922-3935 (2013)

PubMed id: 23647266

Increasing the efficiency of ligands for FK506-binding protein 51 by conformational control.

Y.Wang, A.Kirschner, A.K.Fabian, R.Gopalakrishnan, C.Kress, B.Hoogeland, U.Koch, C.Kozany, A.Bracher, F.Hausch.

ABSTRACT

The design of efficient ligands remains a key challenge in drug discovery. In the quest for lead-like ligands for the FK506-binding protein 51 (FKBP51), we designed two new classes of bicyclic sulfonamides to probe the contribution of conformational energy in these ligands. The [4.3.1] scaffold had consistently higher affinity compared to the [3.3.1] or monocyclic scaffolds, which could be attributed to better preorganization of two key recognition motifs. Surprisingly, the binding of the rigid [4.3.1] scaffold was enthalpy-driven and entropically disfavored compared to the flexible analogues. Cocrystal structures at atomic resolution revealed that the sulfonamide nitrogen in the bicyclic scaffolds can accept an unusual hydrogen bond from Tyr(113) that mimics the putative FKBP transition state. This resulted in the first lead-like, functionally active ligand for FKBP51. Our work exemplifies how atom-efficient ligands can be achieved by careful conformational control even in very open and thus difficult binding sites such as FKBP51.