3OMU

Crystal Structure of the N-terminal domain of an HSP90 from Trypanosoma Brucei, Tb10.26.1080 in the presence of a thienopyrimidine derivative

3OMU の概要

• エントリーDOI: 10.2210/pdb3omu/pdb
• 関連するPDBエントリー: 3O6O
• 分子名称: Heat shock protein 83, 2-amino-4-{2,4-dichloro-5-[2-(diethylamino)ethoxy]phenyl}-N-ethylthieno[2,3-d]pyrimidine-6-carboxamide (3 entities in total)
• 機能のキーワード: hsp90, trypanosoma bruceii, structural genomics, drug discovery, structural genomics consortium, sgc, chaperone
• 由来する生物種: Trypanosoma brucei
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 53365.62

構造登録者

Wernimont, A.K.,Hutchinson, A.,Sullivan, H.,Weadge, J.,Cossar, D.,Li, Y.,Kozieradzki, I.,Bochkarev, A.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Weigelt, J.,Wyatt, P.G.,Fairlamb, A.H.,MacKenzie, C.,Ferguson, M.A.J.,Hui, R.,Pizarro, J.C.,Hills, T.,Structural Genomics Consortium (SGC) (登録日: 2010-08-27, 公開日: 2010-10-27, 最終更新日: 2024-10-16)

主引用文献

Pizarro, J.C.,Hills, T.,Senisterra, G.,Wernimont, A.K.,Mackenzie, C.,Norcross, N.R.,Ferguson, M.A.,Wyatt, P.G.,Gilbert, I.H.,Hui, R.
Exploring the Trypanosoma brucei Hsp83 potential as a target for structure guided drug design.
PLoS Negl Trop Dis, 7:e2492-e2492, 2013

PubMed Abstract: Human African trypanosomiasis is a neglected parasitic disease that is fatal if untreated. The current drugs available to eliminate the causative agent Trypanosoma brucei have multiple liabilities, including toxicity, increasing problems due to treatment failure and limited efficacy. There are two approaches to discover novel antimicrobial drugs--whole-cell screening and target-based discovery. In the latter case, there is a need to identify and validate novel drug targets in Trypanosoma parasites. The heat shock proteins (Hsp), while best known as cancer targets with a number of drug candidates in clinical development, are a family of emerging targets for infectious diseases. In this paper, we report the exploration of T. brucei Hsp83--a homolog of human Hsp90--as a drug target using multiple biophysical and biochemical techniques. Our approach included the characterization of the chemical sensitivity of the parasitic chaperone against a library of known Hsp90 inhibitors by means of differential scanning fluorimetry (DSF). Several compounds identified by this screening procedure were further studied using isothermal titration calorimetry (ITC) and X-ray crystallography, as well as tested in parasite growth inhibitions assays. These experiments led us to the identification of a benzamide derivative compound capable of interacting with TbHsp83 more strongly than with its human homologs and structural rationalization of this selectivity. The results highlight the opportunities created by subtle structural differences to develop new series of compounds to selectively target the Trypanosoma brucei chaperone and effectively kill the sleeping sickness parasite.

PubMed: 24147171
DOI: 10.1371/journal.pntd.0002492

実験手法

X-RAY DIFFRACTION (2.15 Å)