Human dihydrofolate reductase complexed with ligands

This figure shows the X-ray crystal structure of the human enzyme with bound NADPH (yellow) and methotrexate (red).

The additional amino group on methotrexate allows formation of an additional hydrogen bond to the enzyme, which increases its binding affinity to the folate binding site.

These two ligands bind such that the pyridine ring of NADPH is in close proximity to the pteridine ring of the folate ligand, as required for the hydride transfer catalyzed by this enzyme.

Notice that the folate binds in a bent, rather than linear, form.