6TX6

CRYSTAL STRUCTURE OF HUMAN FKBP51 FK1 DOMAIN A19T MUTANT IN COMPLEX WITH NICOTINAMIDE

6TX6 の概要

• エントリーDOI: 10.2210/pdb6tx6/pdb
• 分子名称: Peptidyl-prolyl cis-trans isomerase FKBP5, CHLORIDE ION, SODIUM ION, ... (5 entities in total)
• 機能のキーワード: ppiase, fragment, isomerase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 14351.76

構造登録者

Fiegen, D.,Draxler, S.W. (登録日: 2020-01-13, 公開日: 2020-05-27, 最終更新日: 2024-01-24)

主引用文献

Draxler, S.W.,Bauer, M.,Eickmeier, C.,Nadal, S.,Nar, H.,Rangel Rojas, D.,Seeliger, D.,Zeeb, M.,Fiegen, D.
Hybrid Screening Approach for Very Small Fragments: X-ray and Computational Screening on FKBP51.
J.Med.Chem., 63:5856-5864, 2020

PubMed 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 N 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 N HSQC NMR based KD determination to rapidly identify hits and their binding poses.

PubMed: 32420743
DOI: 10.1021/acs.jmedchem.0c00120

実験手法

X-RAY DIFFRACTION (0.98 Å)