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Science 23 January 1987:
Vol. 235. no. 4787, pp. 448 - 455
DOI: 10.1126/science.3099389
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Articles

Science, Vol 235, Issue 4787, 448-455
Copyright © 1987 by American Association for the Advancement of Science

articles

Atomic structure of thymidylate synthase: target for rational drug design

LW Hardy, JS Finer-Moore, WR Montfort, MO Jones, DV Santi, and RM Stroud

The atomic structure of thymidylate synthase from Lactobacillus casei was determined at 3 angstrom resolution. The native enzyme is a dimer of identical subunits. The dimer interface is formed by an unusual association between five-stranded beta sheets present in each monomer. Comparison of known sequences with the Lactobacillus casei structure suggests that they all have a common core structure around which loops are inserted or deleted in different sequences. Residues from both subunits contribute to each active site. Two arginine side chains can contribute to binding phosphate on the substrate. The side chains of several conserved amino acids can account for other determinants of substrate binding.


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