4YRO

Crystal structure of T. cruzi Histidyl-tRNA synthetase in complex with 5-bromo-6-methylpyridin-2-amine (Chem 491)

4YRO の概要

• エントリーDOI: 10.2210/pdb4yro/pdb
• 関連するPDBエントリー: 4YP0 4YPF 4YRC 4YRE 4YRF 4YRG 4YRI 4YRJ 4YRK 4YRL 4YRM 4YRN 4YRP 4YRQ 4YRR 4YRS 4YRT
• 分子名称: Histidyl-tRNA synthetase, HISTIDINE, 5-bromo-6-methylpyridin-2-amine, ... (7 entities in total)
• 機能のキーワード: ligase, aminoacyl-trna synthetase, aars, hisrs, trypanosoma cruzi, protein-inhibitor complex, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• 由来する生物種: Trypanosoma cruzi (strain CL Brener)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 52097.38

構造登録者

Koh, C.-Y.,Hol, W.G.J. (登録日: 2015-03-15, 公開日: 2015-08-12, 最終更新日: 2023-09-27)

主引用文献

Koh, C.Y.,Siddaramaiah, L.K.,Ranade, R.M.,Nguyen, J.,Jian, T.,Zhang, Z.,Gillespie, J.R.,Buckner, F.S.,Verlinde, C.L.,Fan, E.,Hol, W.G.
A binding hotspot in Trypanosoma cruzi histidyl-tRNA synthetase revealed by fragment-based crystallographic cocktail screens.
Acta Crystallogr. D Biol. Crystallogr., 71:1684-1698, 2015

PubMed Abstract: American trypanosomiasis, commonly known as Chagas disease, is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. The chronic form of the infection often causes debilitating morbidity and mortality. However, the current treatment for the disease is typically inadequate owing to drug toxicity and poor efficacy, necessitating a continual effort to discover and develop new antiparasitic therapeutic agents. The structure of T. cruzi histidyl-tRNA synthetase (HisRS), a validated drug target, has previously been reported. Based on this structure and those of human cytosolic HisRS, opportunities for the development of specific inhibitors were identified. Here, efforts are reported to identify small molecules that bind to T. cruzi HisRS through fragment-based crystallographic screening in order to arrive at chemical starting points for the development of specific inhibitors. T. cruzi HisRS was soaked into 68 different cocktails from the Medical Structural Genomics of Pathogenic Protozoa (MSGPP) fragment library and diffraction data were collected to identify bound fragments after soaking. A total of 15 fragments were identified, all bound to the same site on the protein, revealing a fragment-binding hotspot adjacent to the ATP-binding pocket. On the basis of the initial hits, the design of reactive fragments targeting the hotspot which would be simultaneously covalently linked to a cysteine residue present only in trypanosomatid HisRS was initiated. Inhibition of T. cruzi HisRS was observed with the resultant reactive fragments and the anticipated binding mode was confirmed crystallographically. These results form a platform for the development of future generations of selective inhibitors for trypanosomatid HisRS.

PubMed: 26249349
DOI: 10.1107/S1399004715007683

実験手法

X-RAY DIFFRACTION (2.5 Å)