The Z isomer of 2,4-diaminofuro[2,3-d]pyrimidine antifolate promotes unusual crystal packing in a human dihydrofolate reductase ternary complex

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 P2₁2₁2₁ and its structure was refined to 1.7 Å 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 P2₁ and shows that Gln35 interacts with Arg70.