Download MendeleyThe structure of Cryptococcus neoformans thymidylate synthase suggests strategies for using target dynamics for species-specific inhibition.
Finer-Moore, J.S., Anderson, A.C., O'Neil, R.H., Costi, M.P., Ferrari, S., Krucinski, J., Stroud, R.M.(2005) Acta Crystallogr D Biol Crystallogr 61: 1320-1334
- PubMed: 16204883
- DOI: https://doi.org/10.1107/S0907444905022638
- Primary Citation of Related Structures:
2A9W, 2AAZ - PubMed Abstract:
The ternary complex crystal structures of Cryptococcus neoformans and Escherichia coli thymidylate synthase (TS) suggest mechanisms of species-specific inhibition of a highly conserved protein. The 2.1 Angstrom structure of C. neoformans TS cocrystallized with substrate and the cofactor analog CB3717 shows that the binding sites for substrate and cofactor are highly conserved with respect to human TS, but that the structure of the cofactor-binding site of C. neoformans TS is less constrained by surrounding residues. This feature might allow C. neoformans TS to form TS-dUMP-inhibitor complexes with a greater range of antifolates than human TS. 3',3''-Dibromophenol-4-chloro-1,8-naphthalein (GA9) selectively inhibits both E. coli TS and C. neoformans TS (K(i) = 4 microM) over human TS (K(i) >> 245 microM). The E. coli TS-dUMP-GA9 complex is in an open conformation, similar to that of the apoenzyme crystal structure. The GA9-binding site overlaps the binding site of the pABA-glutamyl moiety of the cofactor. The fact that human apoTS can adopt an unusual fold in which the GA9-binding site is disordered may explain the poor affinity of GA9 for the human enzyme. These observations highlight the critical need to incorporate multiple target conformations in any computational attempt to facilitate drug discovery.
Organizational Affiliation:
Department of Biochemistry and Biophysics, University of California, San Francisco, 600 16th Street, Room S412B, San Francisco, CA 94143-2240, USA.
