1mvs
Analysis of Two Polymorphic Forms of a Pyrido[2,3-d]pyrimidine N9-C10 Reverse-Bridge Antifolate Binary Complex with Human Dihydrofolate Reductase
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OverviewOverview
The results of the crystal structure determination of human dihydrofolate, reductase (hDHFR) as a binary complex with the potent N9-C10, reversed-bridge antifolate inhibitor, 2,4-diamino-6-[N-(3',4',5'-trimethoxybenzyl)-N-methylamino]pyrido[2,3-d]py, rimidine (1) are reported for two independent polymorphic rhombohedral R3, lattices [R3(1) and R3(2)]. Data from these two crystal forms were refined, to 1.90 A resolution for complex R3(1), with R = 0.186 for 9689 data, and, to 1.80 A resolution for complex R3(2), with R = 0.194 for 13 305 data., Changes in the loop geometry between the two structures reflects contact, differences in the packing environments in the two R3 lattices. The, largest changes (between 0.5 and 1.7 A) are observed for the loop regions, encompassing residues 16-25, 40-48, 81-89, 99-108, 143-148 and 161-169., Comparison of the intermolecular contacts of these loops reveals that the, R3(2) lattice is more tightly packed, as reflected in its smaller V(M), value and smaller solvent content. The conformation of inhibitor (1) is, similar in both structures and the N9-C10 bridge geometry is more similar, to that observed for the normal C9-N10 bridge of trimetrexate (TMQ) than, to the other N9-C10 reversed-bridge antifolates previously reported. The, effect of the N9-C10 reversed-bridge geometry is to distort the bridge, from coplanarity with the pyrido[2,3-d]pyrimidine ring system and to twist, the C10 methylene conformation towards a gauche conformation. This also, influences the conformation of the methoxybenzyl ring, moving it away from, a trans position and placing the 5'-methoxy group deeper within the, hydrophobic pocket made by Leu60, Pro61 and Asn64 of the hDHFR active, site.
DiseaseDisease
Known disease associated with this structure: Anemia, megaloblastic, due to DHFR deficiency (1) OMIM:[126060]
About this StructureAbout this Structure
1MVS is a Single protein structure of sequence from Homo sapiens with SO4 and DTM as ligands. Active as Dihydrofolate reductase, with EC number 1.5.1.3 Full crystallographic information is available from OCA.
ReferenceReference
Analysis of two polymorphic forms of a pyrido[2,3-d]pyrimidine N9-C10 reversed-bridge antifolate binary complex with human dihydrofolate reductase., Cody V, Galitsky N, Luft JR, Pangborn W, Gangjee A, Acta Crystallogr D Biol Crystallogr. 2003 Apr;59(Pt 4):654-61. Epub 2003, Mar 25. PMID:12657784
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