7QI8

CRYSTAL STRUCTURE OF LYSYL-TRNA SYNTHETASE FROM Mycobacterium tuberculosis COMPLEXED WITH L-LYSINE AND INHIBITOR

Summary for 7QI8

• Entry DOI: 10.2210/pdb7qi8/pdb
• Related: 7QH8 7QHN
• Descriptor: Lysine--tRNA ligase 1, LYSINE, 2-azanyl-6-[(1~{S},7~{S})-2,2-bis(fluoranyl)-7-oxidanyl-cycloheptyl]-4-methoxy-7~{H}-pyrrolo[3,4-d]pyrimidin-5-one, ... (4 entities in total)
• Functional Keywords: ligase, mycobacterium tuberculosis, atp binding
• Biological source: Mycobacterium tuberculosis H37Rv
• Total number of polymer chains: 1
• Total formula weight: 58605.08

Authors

Dawson, A.,Robinson, D.A.,Tamjar, J.,Wyatt, P.,Green, S. (deposition date: 2021-12-14, release date: 2022-10-19, Last modification date: 2024-02-07)

Primary citation

Green, S.R.,Davis, S.H.,Damerow, S.,Engelhart, C.A.,Mathieson, M.,Baragana, B.,Robinson, D.A.,Tamjar, J.,Dawson, A.,Tamaki, F.K.,Buchanan, K.I.,Post, J.,Dowers, K.,Shepherd, S.M.,Jansen, C.,Zuccotto, F.,Gilbert, I.H.,Epemolu, O.,Riley, J.,Stojanovski, L.,Osuna-Cabello, M.,Perez-Herran, E.,Rebollo, M.J.,Guijarro Lopez, L.,Casado Castro, P.,Camino, I.,Kim, H.C.,Bean, J.M.,Nahiyaan, N.,Rhee, K.Y.,Wang, Q.,Tan, V.Y.,Boshoff, H.I.M.,Converse, P.J.,Li, S.Y.,Chang, Y.S.,Fotouhi, N.,Upton, A.M.,Nuermberger, E.L.,Schnappinger, D.,Read, K.D.,Encinas, L.,Bates, R.H.,Wyatt, P.G.,Cleghorn, L.A.T.
Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs.
Nat Commun, 13:5992-5992, 2022

PubMed Abstract: Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described. The series has been developed against M. tuberculosis lysyl-tRNA synthetase (LysRS) and cellular studies support this mechanism of action. DDD02049209, the lead compound, is efficacious in mouse models of acute and chronic tuberculosis and has suitable physicochemical, pharmacokinetic properties and an in vitro safety profile that supports further development. Importantly, preliminary analysis using clinical resistant strains shows no pre-existing clinical resistance towards this scaffold.

PubMed: 36220877
DOI: 10.1038/s41467-022-33736-5

Experimental method

X-RAY DIFFRACTION (2.2 Å)