3GYF

Human DHFR with Z-isomer in Orthorhombic lattice

Summary for 3GYF

• Entry DOI: 10.2210/pdb3gyf/pdb
• Related: 1u72 3d7x
• Descriptor: Dihydrofolate reductase, 5-[(1Z)-2-(2-methoxyphenyl)prop-1-en-1-yl]furo[2,3-d]pyrimidine-2,4-diamine, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (5 entities in total)
• Functional Keywords: human dihydrofolate reductase packing, z-isomer furopyrimidine, nadp, one-carbon metabolism, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 22810.66

Authors

Cody, V. (deposition date: 2009-04-03, release date: 2009-11-03, Last modification date: 2023-09-06)

Primary citation

Cody, V.,Pace, J.,Lin, L.,Gangjee, A.
The Z isomer of 2,4-diaminofuro[2,3-d]pyrimidine antifolate promotes unusual crystal packing in a human dihydrofolate reductase ternary complex.
Acta Crystallogr.,Sect.F, 65:762-766, 2009

PubMed Abstract: The crystal structure of the ternary complex of human dihydrofolate reductase (hDHFR) with NADPH and the Z isomer of 2,4-diamino-5-[2-(2'-methoxyphenyl)propenyl]-furo[2,3-d]pyrimidine (Z1) shows that the Z isomer binds in the normal antifolate orientation in which the furo oxygen occupies the 8-amino position observed in the binding of 2,4-diaminopteridine antifolates such as methotrexate and with the methoxyphenyl moiety cis to and coplanar with the furo[2,3-d]pyrimidine ring. The hDHFR ternary complex crystallized in the orthorhombic space group P2(1)2(1)2(1) and its structure was refined to 1.7 A resolution. Although other hDHFR complexes crystallize in this space group, these data provide only the second example of an unusual packing arrangement in which the conserved active-site Arg70 forms a salt bridge to the side chain of Glu44 from a symmetry-related molecule. As a result, the conformations of Phe31 and Gln35 shift with respect to those observed in the structure of mouse DHFR bound to Z1, which crystallizes in the monoclinic space group P2(1) and shows that Gln35 interacts with Arg70.

PubMed: 19652333
DOI: 10.1107/S1744309109025548

Experimental method

X-RAY DIFFRACTION (1.7 Å)