1s3y
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Structure Determination of Tetrahydroquinazoline Antifolates in Complex with Human and Pneumocystis carinii Dihydrofolate Reductase: Correlations of Enzyme Selectivity and Stereochemistry
OverviewOverview
Structural data are reported for the first examples of the, tetrahydroquinazoline antifolate, (6R,6S)-2,4-diamino-6-(1-indolinomethyl)-5,6,7,8-tetrahydroquinazoline (1), and its trimethoxy analogue, (6R,6S)-2,4-diamino-6-(3',4',5'-trimethoxybenzyl)-5,6,7,8-tetrahydroquinaz, oline (2) as inhibitor complexes with dihydrofolate reductase (DHFR) from, human (hDHFR) and Pneumocystis carinii (pcDHFR) sources. The indoline, analogue (1) was crystallized as ternary complexes with NADPH and hDHFR, (1.9 A resolution) and pcDHFR (2.3 A resolution), while the trimethoxy, quinazoline analogue (2) was crystallized as a binary complex with hDHFR, in two polymorphic rhombohedral R3 lattices: R3(1) to 1.8 A resolution and, R3(2) to 2.0 A resolution. Structural analysis of these potent and, selective DHFR-inhibitor complexes revealed preferential binding of the, 6S-equatorial isomer in each structure. This configuration is similar to, that of the natural tetrahydrofolate substrate; that is, 6S. These data, also show that in both the hDHFR and pcDHFR ternary complexes with (1) the, indoline ring is partially disordered, with two static conformations that, differ between structures. These conformers also differ from that observed, for the trimethoxybenzyl ring of tetrahydroquinazoline (2). There is also, a correlation between the disorder of the flexible loop 23 and the, disorder of the cofactor nicotinamide ribose ring in the pcDHFR-NADPH-(1), ternary complex. Comparison of the Toxoplasma gondii DHFR (tgDHFR), sequence with those of other DHFRs provides insight into the role of, sequence and conformation in inhibitor-binding preferences which may aid, in the design of novel antifolates with specific DHFR selectivity.
About this StructureAbout this Structure
1S3Y is a Single protein structure of sequence from Pneumocystis carinii with NAP and TQT as ligands. Active as Dihydrofolate reductase, with EC number 1.5.1.3 Full crystallographic information is available from OCA.
ReferenceReference
Structure determination of tetrahydroquinazoline antifolates in complex with human and Pneumocystis carinii dihydrofolate reductase: correlations between enzyme selectivity and stereochemistry., Cody V, Luft JR, Pangborn W, Gangjee A, Queener SF, Acta Crystallogr D Biol Crystallogr. 2004 Apr;60(Pt 4):646-55. Epub 2004, Mar 23. PMID:15039552
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