Structure determination of Pneumocystis carinii dihydrofolate reductase complex (Meeting abstract).

Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.

Structure determination of Pneumocystis carinii dihydrofolate reductase complex (Meeting abstract).

Proc Annu Meet Am Assoc Cancer Res; 36:A2429 1995. Unique Identifier : AIDSLINE ICDB/95610203
Cody V; Galitsky N; Luft JR; Pangborn W; Hauptman-Woodward Medical Research Inst., Inc., Buffalo, NY 14203

Abstract: Pneumonia caused by opportunistic infectious agents is a major cause of mortality among patients with AIDS. Antifolates have been shown effective against the dihydrofolate reductase (DHFR) from Pneumocystis carinii (Pc) which is a target for drug design studies. Crystals of recombinant Pc DHFR ternary complex with the novel fluropyrimidine antifolate and NADPH are monoclinic, space group P21, with lattice constants of a = 37.171, b = 43.094, c = 61.049A and beta = 94.847 degrees and diffract to 2.5A resolution. The structure was solved by molecular replacement methods to phase the structure using coordinates from human DHFR. Analysis of the electron density map revealed a conserved active site and shows the 20 extra residues in Pc DHFR compared to the human enzyme are located in flexible loop regions away from the active site. The substitution of position F31 in human by isoleucine in Pc and N64 to phenylalanine cause little change in the active site interactions. There is a loss of one hydrogen bond to the folate by the N64F change in Pc. The human P25 deletion and P26K substitution in Pc results in shifts in the cofactor-inhibitor interactions.

Keywords: AIDS-Related Opportunistic Infections/MICROBIOLOGY Human Molecular Structure Pneumocystis carinii/*ENZYMOLOGY Pneumonia, Pneumocystis carinii/MICROBIOLOGY Tetrahydrofolate Dehydrogenase/*CHEMISTRY ABSTRACT
950930
M9591321

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