4KY4

Crystal structure of non-classical TS inhibitor 2 in complex with Toxoplasma gondii TS-DHFR

Summary for 4KY4

• Entry DOI: 10.2210/pdb4ky4/pdb
• Related: 4EIL 4KYA
• Descriptor: Bifunctional dihydrofolate reductase-thymidylate synthase, 2'-DEOXYURIDINE 5'-MONOPHOSPHATE, Aminopterin, ... (5 entities in total)
• Functional Keywords: synthase, bifunctional, oxidoreductase, transferase
• Biological source: Toxoplasma gondii
• Total number of polymer chains: 8
• Total formula weight: 565160.24

Authors

Sharma, H.,Anderson, K.S. (deposition date: 2013-05-28, release date: 2014-08-06, Last modification date: 2023-09-20)

Primary citation

Zaware, N.,Sharma, H.,Yang, J.,Devambatla, R.K.,Queener, S.F.,Anderson, K.S.,Gangjee, A.
Discovery of potent and selective inhibitors of Toxoplasma gondii thymidylate synthase for opportunistic infections.
ACS Med Chem Lett, 4:1148-1151, 2013

PubMed Abstract: Infection by the parasite (tg) can lead to toxoplasmosis in immunocompromised patients such as organ transplant, cancer and HIV/AIDS patients. The bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) enzyme is crucial for nucleotide synthesis in , and represents a potential target to combat infection. While species selectivity with drugs has been attained for DHFR, TS is much more conserved across species and specificity is significantly more challenging. We discovered novel substituted-9-pyrimido[4,5-]indoles - with single-digit nanomolar K for tgTS, two of which, and , are 28- and 122-fold selective over human TS (hTS). The synthesis of these compounds, and their structures in complex with tgTS-DHFR are presented along with binding measurements and cell culture data. These results show, for the very first time, that in spite of the high degree of conservation of active site residues between hTS and the parasite TS, specificity has been accomplished via novel structures and provides a new target (TS) for selective drug development against parasitic infections.

PubMed: 24470841
DOI: 10.1021/ml400208v

Experimental method

X-RAY DIFFRACTION (2.79 Å)