Hydrophobic interactions of a substrate with <scp>L193</scp> on the flexible substrate‐binding loop contribute to 3α‐hydroxysteroid dehydrogenase/carbonyl reductase catalytic efficiency

and substrate binding promote loop closure and strengthen hydrophobic interactions involving L193 in the active site. These data establish that the hydrophobic interaction of residue 193 with the transition state of substrate, linked to remote binding interactions of the loop with the unreactive portion of the substrate, significantly contributes to 3α-HSD/CR catalysis.