7qi8

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

Structural highlights

7qi8 is a 1 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SYK1_MYCTO

Publication Abstract from PubMed

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.

Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs.,Green SR, Davis SH, Damerow S, Engelhart CA, Mathieson M, Baragana B, Robinson DA, Tamjar J, Dawson A, Tamaki FK, Buchanan KI, Post J, Dowers K, Shepherd SM, Jansen C, Zuccotto F, Gilbert IH, Epemolu O, Riley J, Stojanovski L, Osuna-Cabello M, Perez-Herran E, Rebollo MJ, Guijarro Lopez L, Casado Castro P, Camino I, Kim HC, Bean JM, Nahiyaan N, Rhee KY, Wang Q, Tan VY, Boshoff HIM, Converse PJ, Li SY, Chang YS, Fotouhi N, Upton AM, Nuermberger EL, Schnappinger D, Read KD, Encinas L, Bates RH, Wyatt PG, Cleghorn LAT Nat Commun. 2022 Oct 11;13(1):5992. doi: 10.1038/s41467-022-33736-5. PMID:36220877^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Green SR, Davis SH, Damerow S, Engelhart CA, Mathieson M, Baragana B, Robinson DA, Tamjar J, Dawson A, Tamaki FK, Buchanan KI, Post J, Dowers K, Shepherd SM, Jansen C, Zuccotto F, Gilbert IH, Epemolu O, Riley J, Stojanovski L, Osuna-Cabello M, Perez-Herran E, Rebollo MJ, Guijarro Lopez L, Casado Castro P, Camino I, Kim HC, Bean JM, Nahiyaan N, Rhee KY, Wang Q, Tan VY, Boshoff HIM, Converse PJ, Li SY, Chang YS, Fotouhi N, Upton AM, Nuermberger EL, Schnappinger D, Read KD, Encinas L, Bates RH, Wyatt PG, Cleghorn LAT. Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs. Nat Commun. 2022 Oct 11;13(1):5992. doi: 10.1038/s41467-022-33736-5. PMID:36220877 doi:http://dx.doi.org/10.1038/s41467-022-33736-5

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OCA

[1] Green SR, Davis SH, Damerow S, Engelhart CA, Mathieson M, Baragana B, Robinson DA, Tamjar J, Dawson A, Tamaki FK, Buchanan KI, Post J, Dowers K, Shepherd SM, Jansen C, Zuccotto F, Gilbert IH, Epemolu O, Riley J, Stojanovski L, Osuna-Cabello M, Perez-Herran E, Rebollo MJ, Guijarro Lopez L, Casado Castro P, Camino I, Kim HC, Bean JM, Nahiyaan N, Rhee KY, Wang Q, Tan VY, Boshoff HIM, Converse PJ, Li SY, Chang YS, Fotouhi N, Upton AM, Nuermberger EL, Schnappinger D, Read KD, Encinas L, Bates RH, Wyatt PG, Cleghorn LAT. Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs. Nat Commun. 2022 Oct 11;13(1):5992. doi: 10.1038/s41467-022-33736-5. PMID:36220877 doi:http://dx.doi.org/10.1038/s41467-022-33736-5

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