3NZC

Structural Analysis of Pneumocystis carinii and Human DHFR Complexes with NADPH and a Series of Five Potent 5-(omega-carboxy(alkyloxy)pyrido[2,3-d]pyridine Derivativea

Summary for 3NZC

• Entry DOI: 10.2210/pdb3nzc/pdb
• Related: 2fzh 2fzi 2fzj 3NXO 3NXR 3NXT 3NXV 3NXX 3NXY 3NZ6 3NZ9 3NZA 3NZB 3NZD
• Descriptor: Dihydrofolate reductase, 6-[2-methoxy-5-(2-phenylethoxy)benzyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine, PHOSPHATE ION, ... (5 entities in total)
• Functional Keywords: pneumocystis carinii dhfr inhibitor complexes, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Pneumocystis carinii
• Total number of polymer chains: 1
• Total formula weight: 24613.18

Authors

Cody, V. (deposition date: 2010-07-16, release date: 2010-12-29, Last modification date: 2023-09-06)

Primary citation

Cody, V.,Pace, J.
Structural analysis of Pneumocystis carinii and human DHFR complexes with NADPH and a series of five potent 6-[5'-([omega]-carboxyalkoxy)benzyl]pyrido[2,3-d]pyrimidine derivatives
Acta Crystallogr.,Sect.D, 67:1-7, 2011

PubMed Abstract: Structural data are reported for five antifolates, namely 2,4-diamino-6-[5'-(5-carboxypentyloxy)-2'-methoxybenzyl]-5-methylpyrido[2,3-d]pyrimidine, (1), and the 5'-[3-(ethoxycarbonyl)propoxy]-, (2), 5'-[3-(ethoxycarbonyl)butoxy]-, (3), 5'-[3-(ethoxycarbonyl)pentyloxy]-, (4), and 5'-benzyloxy-, (5), derivatives, which are potent and selective for Pneumocystis carinii dihydrofolate reductase (pcDHFR). Crystal structures are reported for their ternary complexes with NADPH and pcDHFR refined to between 1.4 and 2.0 Å resolution and for that of 3 with human DHFR (hDHFR) to 1.8 Å resolution. These data reveal that the carboxylate of the ω-carboxyalkoxy side chain of 1, the most potent inhibitor in this series, forms ionic interactions with the conserved Arg75 in the substrate-binding pocket of pcDHFR, whereas the less potent ethyl esters of 2-4 bind with variable side-chain conformations. The benzyloxy side chain of 5 makes no contact with Arg75 and is the least active inhibitor in this series. These structural results suggest that the weaker binding of this series compared with that of their pyrimidine homologs in part arises from the flexibility observed in their side-chain conformations, which do not optimize intermolecular contact to Arg75. Structural data for the binding of 3 to both hDHFR and pcDHFR reveals that the inhibitor binds in two different conformations, one similar to each of the two conformations observed for the parent pyrido[2,3-d]pyrimidine, piritrexim (PTX), bound to hDHFR. The structure of the pcDHFR complex of 4 reveals disorder in the side-chain orientation; one orientation has the ω-carboxyalkoxy side chain positioned in the folate-binding pocket similar to the others in this series, while the second orientation occupies a new site near the nicotinamide ring of NADPH. This alternate binding site has not been observed in other DHFR structures. Structural data for the pcDHFR complex of 5 show that its benzyl side chain forms intermolecular van der Waals interactions with Phe69 in the binding pocket that could account for its enhanced binding selectivity compared with the other analogs in this series.

PubMed: 21206056
DOI: 10.1107/S0907444910041004

Experimental method

X-RAY DIFFRACTION (2 Å)