PDBsum entry 6tx7

Isomerase

PDB id: 6tx7

Contents

Protein chain

128 a.a.

Ligands

V1L ×2

Metals

_CL

_NA ×2

Waters ×172

PDB id:

6tx7

Name:

Isomerase

Title:

Crystal structure of human fkbp51 fk1 domain a19t mutant in complex with 2-piperidone

Structure:

Peptidyl-prolyl cis-trans isomerase fkbp5. Chain: a. Synonym: ppiase fkbp5,51 kda fk506-binding protein,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

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: fkbp5, aig6, fkbp51. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.13Å R-factor: 0.128 R-free: 0.152

Authors:

D.Fiegen,S.W.Draxler

Key ref:

S.W.Draxler et al. (2020). Hybrid Screening Approach for Very Small Fragments: X-ray and Computational Screening on FKBP51. J Med Chem, 63, 5856-5864. PubMed id: 32420743 DOI: 10.1021/acs.jmedchem.0c00120

Date:

13-Jan-20 Release date: 27-May-20

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/acs.jmedchem.0c00120

J Med Chem 63:5856-5864 (2020)

PubMed id: 32420743

Hybrid Screening Approach for Very Small Fragments: X-ray and Computational Screening on FKBP51.

S.W.Draxler, M.Bauer, C.Eickmeier, S.Nadal, H.Nar, D.Rangel Rojas, D.Seeliger, M.Zeeb, D.Fiegen.

ABSTRACT

Fragment-based drug discovery (FBDD) permits efficient sampling of the vast chemical space for hit identification. Libraries are screened biophysically and fragment:protein co-structures are determined by X-ray crystallography. In parallel, computational methods can derive pharmacophore models or screen virtual libraries. We screened 15 very small fragments (VSFs) (HA ≤ 11) computationally, using site identification by ligand competitive saturation (SILCS), and experimentally, by X-ray crystallography, to map potential interaction sites on the FKBP51 FK1 domain. We identified three hot spots and obtained 6 X-ray co-structures, giving a hit rate of 40%. SILCS FragMaps overlapped with X-ray structures. The compounds had millimolar affinities as determined by ¹⁵N HSQC NMR. VSFs identified the same interactions as known FK1 binder and provide new chemical starting points. We propose a hybrid screening strategy starting with SILCS, followed by a pharmacophore-derived X-ray screen and ¹⁵N HSQC NMR based KD determination to rapidly identify hits and their binding poses.