3NXV

Preferential Selection of Isomer Binding from Chiral Mixtures: Alternate Binding Modes Observed for the E- and Z-isomers of a Series of 5-Substituted 2,4-Diaminofuro[2,3-d]pyrimidines as Ternary Complexes with NADPH and Human Dihydrofolate Reductase

Summary for 3NXV

• Entry DOI: 10.2210/pdb3nxv/pdb
• Related: 3NXO 3NXR 3NXT 3NXX 3NXY 3NZ6 3NZ9 3NZA 3NZB 3NZC 3NZD 3d7x 3d7y 3gyf
• Descriptor: Dihydrofolate reductase, 5-[(1E)-2-(2-methoxyphenyl)hex-1-en-1-yl]furo[2,3-d]pyrimidine-2,4-diamine, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (5 entities in total)
• Functional Keywords: chiral mixture, e-z-isomers, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Mitochondrion : P00374
• Total number of polymer chains: 1
• Total formula weight: 22529.41

Authors

Cody, V. (deposition date: 2010-07-14, release date: 2010-12-01, Last modification date: 2024-04-03)

Primary citation

Cody, V.,Piraino, J.,Pace, J.,Li, W.,Gangjee, A.
Preferential selection of isomer binding from chiral mixtures: alternate binding modes observed for the E and Z isomers of a series of 5-substituted 2,4-diaminofuro[2,3-d]pyrimidines as ternary complexes with NADPH and human dihydrofolate reductase.
Acta Crystallogr.,Sect.D, 66:1271-1277, 2010

PubMed Abstract: The crystal structures of six human dihydrofolate reductase (hDHFR) ternary complexes with NADPH and a series of mixed E/Z isomers of 5-substituted 5-[2-(2-methoxyphenyl)-prop-1-en-1-yl]furo[2,3-d]pyrimidine-2,4-diamines substituted at the C9 position with propyl, isopropyl, cyclopropyl, butyl, isobutyl and sec-butyl (E2-E7, Z3) were determined and the results were compared with the resolved E and Z isomers of the C9-methyl parent compound. The configuration of all of the inhibitors, save one, was observed as the E isomer, in which the binding of the furopyrimidine ring is flipped such that the 4-amino group binds in the 4-oxo site of folate. The Z3 isomer of the C9-isopropyl analog has the normal 2,4-diaminopyrimidine ring binding geometry, with the furo oxygen near Glu30 and the 4-amino group interacting near the cofactor nicotinamide ring. Electron-density maps for these structures revealed the binding of only one isomer to hDHFR, despite the fact that chiral mixtures (E:Z ratios of 2:1, 3:1 and 3:2) of the inhibitors were incubated with hDHFR prior to crystallization. Superposition of the hDHFR complexes with E2 and Z3 shows that the 2'-methoxyphenyl ring of E2 is perpendicular to that of Z3. The most potent inhibitor in this series is the isopropyl analog Z3 and the least potent is the isobutyl analog E6, consistent with data that show that the Z isomer makes the most favorable interactions with the active-site residues. The isobutyl moiety of E6 is observed in two orientations and the resultant steric crowding of the E6 analog is consistent with its weaker activity. The alternative binding modes observed for the furopyrimidine ring in these E/Z isomers suggest that new templates can be designed to probe these binding regions of the DHFR active site.

PubMed: 21123866
DOI: 10.1107/S0907444910035808

Experimental method

X-RAY DIFFRACTION (1.9 Å)