3td8

Structural Analysis of Pneumocystis carinii Dihydrofolate Reductase Complex with NADPH and 2,4-diamino-5-methyl-6-[2'-(4-carboxy-1-pentynyl)-5'-methoxybenzyl]pyrido[2,3-d]pyrimidineStructural Analysis of Pneumocystis carinii Dihydrofolate Reductase Complex with NADPH and 2,4-diamino-5-methyl-6-[2'-(4-carboxy-1-pentynyl)-5'-methoxybenzyl]pyrido[2,3-d]pyrimidine

Structural highlights 3td8 is a 1 chain structure with sequence from Pneca. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: , Related: 3cd2 Activity: Dihydrofolate reductase, with EC number 1.5.1.3 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [DYR_PNECA] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Publication Abstract from PubMed Structural data are reported for 2,4-diamino-6-[2-(5-carboxypent-1-yn-1-yl)-5-methoxybenzyl]-5-methylpyrido[2,3-d] pyrimidine (PY1014) complexed with Pneumocystis carinii dihydrofolate reductase (pcDHFR) refined to 1.8 A resolution. These data reveal that the carboxylate of the omega-carboxyalkynyl side chain of PY1014, the most pcDHFR-selective analog in this series, forms ionic interactions with the conserved Arg75 in the substrate-binding pocket of pcDHFR. The reversal of the 2',5'-substitution pattern of this analog compared with the highly selective diaminopyrimidine analog PY1011 (i.e. the 5'-pentynylcarboxy-5'-methoxy pattern of PY1014 versus the 3',4'-dimethoxy-5'-pentynylcarboxy pattern of PY1011) is necessary to achieve optimal interaction with Arg75 as observed in other structures. The larger diaminopyrido[2,3-d]pyrimidine ring of PY1014 places the 5'-methoxy group closer to Leu25 and Ser64 than does the diaminopyrimidine ring of PY1011. The 5'-methoxy O atom forms a hydrogen bond to the amide of Leu25 (O...N, 2.7 A) and the 5'-methoxy methyl group makes a hydrophobic contact of 3.1 A with C(beta) of Ser64. Although the IC(50) values of PY1014 and PY1011 are similar, inhibition data show that the selectivity of PY1011 for pcDHFR is significantly greater. The greater selectivity for pcDHFR compared with mammalian DHFR of these inhibitors is also influenced by the enhanced hydrophobic interactions of the side-chain methylene atoms with Phe69 of pcDHFR compared with Asn64 of mammalian DHFR. Structural analysis of Pneumocystis cariniidihydrofolate reductase complexed with NADPH and 2,4-diamino-6-[2-(5-carboxypent-1-yn-1-yl)-5-methoxybenzyl]-5-methylpyrido[2,3-d] pyrimidine.,Cody V, Pace J, Stewart E Acta Crystallogr Sect F Struct Biol Cryst Commun. 2012 Apr 1;68(Pt 4):418-23., Epub 2012 Mar 28. PMID:22505410 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Dihydrofolate reductase

spinqualitylabelsall models 3td8, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image