2WSA

Crystal Structure of Leishmania major N-myristoyltransferase (NMT) with bound myristoyl-CoA and a pyrazole sulphonamide ligand (DDD85646)

2WSA の概要

• エントリーDOI: 10.2210/pdb2wsa/pdb
• 分子名称: GLYCYLPEPTIDE N-TETRADECANOYLTRANSFERASE, TETRADECANOYL-COA, 2,6-dichloro-4-(2-piperazin-1-ylpyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzenesulfonamide, ... (4 entities in total)
• 機能のキーワード: acyltransferase, transferase, drug discovery
• 由来する生物種: LEISHMANIA MAJOR
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 52000.55

構造登録者

Robinson, D.A.,Brand, S.,Fairlamb, A.H.,Ferguson, M.A.J.,Frearson, J.A.,Wyatt, P.G.,Structural Genomics Consortium (SGC) (登録日: 2009-09-04, 公開日: 2010-03-23, 最終更新日: 2023-12-20)

主引用文献

Frearson, J.A.,Brand, S.,Cleghorn, L.A.T.,Mcelroy, S.,Smid, O.,Stojanovski, L.,Torrie, L.,Robinson, D.A.,Hallyburton, I.,Guther, M.L.,Price, H.P.,Mpamhanga, C.P.,Brannigan, J.A.,Hodgkinson, M.,Raimi, O.,Van Aalten, D.M.F.,Brenk, R.,Gilbert, I.H.,Read, K.D.,Fairlamb, A.H.,Ferguson, M.A.J.,Smith, D.F.,Wyatt, P.G.
N-Myristoyltransferase Inhibitors as New Leads to Treat Sleeping Sickness.
Nature, 464:728-, 2010

PubMed Abstract: African sleeping sickness or human African trypanosomiasis, caused by Trypanosoma brucei spp., is responsible for approximately 30,000 deaths each year. Available treatments for this disease are poor, with unacceptable efficacy and safety profiles, particularly in the late stage of the disease when the parasite has infected the central nervous system. Here we report the validation of a molecular target and the discovery of associated lead compounds with the potential to address this lack of suitable treatments. Inhibition of this target-T. brucei N-myristoyltransferase-leads to rapid killing of trypanosomes both in vitro and in vivo and cures trypanosomiasis in mice. These high-affinity inhibitors bind into the peptide substrate pocket of the enzyme and inhibit protein N-myristoylation in trypanosomes. The compounds identified have promising pharmaceutical properties and represent an opportunity to develop oral drugs to treat this devastating disease. Our studies validate T. brucei N-myristoyltransferase as a promising therapeutic target for human African trypanosomiasis.

PubMed: 20360736
DOI: 10.1038/NATURE08893

実験手法

X-RAY DIFFRACTION (1.6 Å)