6OJU

Crystal structure of human thymidylate synthase Delta (7-29) in complex with dUMP and 2-amino-4-oxo-4,7-dihydro-pyrrolo[2,3-d]pyrimidine-methyl-phenyl-D-glutamic acid

Summary for 6OJU

• Entry DOI: 10.2210/pdb6oju/pdb
• Descriptor: Thymidylate synthase,Thymidylate synthase, 2'-DEOXYURIDINE 5'-MONOPHOSPHATE, N-{4-[(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl]benzene-1-carbonyl}-D-glutamic acid, ... (4 entities in total)
• Functional Keywords: inhibitor, ts-dhfr, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 135642.54

Authors

Czyzyk, D.J.,Anderson, K.S.,Valhondo, M.,Jorgensen, W.L. (deposition date: 2019-04-12, release date: 2019-06-19, Last modification date: 2023-10-11)

Primary citation

Czyzyk, D.J.,Valhondo, M.,Jorgensen, W.L.,Anderson, K.S.
Understanding the structural basis of species selective, stereospecific inhibition for Cryptosporidium and human thymidylate synthase.
Febs Lett., 593:2069-2078, 2019

PubMed Abstract: Thymidylate synthase (TS), found in all organisms, is an essential enzyme responsible for the de novo synthesis of deoxythymidine monophosphate. The TS active sites of the protozoal parasite Cryptosporidium hominis and human are relatively conserved. Evaluation of antifolate compound 1 and its R-enantiomer 2 against both enzymes reveals divergent inhibitor selectivity and enzyme stereospecificity. To establish how C. hominis and human TS (ChTS and hTS) selectively discriminate 1 and 2, respectively, we determined crystal structures of ChTS complexed with 2 and hTS complexed with 1 or 2. Coupled with the previously determined structure of ChTS complexed with 1, we discuss a possible mechanism for enzyme stereospecificity and inhibitor selectivity.

PubMed: 31172516
DOI: 10.1002/1873-3468.13474

Experimental method

X-RAY DIFFRACTION (2.884 Å)