Engineering an improved crystal contact across a solvent‐mediated interface of human fibroblast growth factor 1

Large‐volume protein crystals are a prerequisite for neutron diffraction studies and their production represents a bottleneck in obtaining neutron structures. Many protein crystals that permit the collection of high‐resolution X‐ray diffraction data are inappropriate for neutron diffraction owing to a plate‐type morphology that limits the crystal volume. Human fibroblast growth factor 1 crystallizes in a plate morphology that yields atomic resolution X‐ray diffraction data but has insufficient volume for neutron diffraction. The thin physical dimension has been identified as corresponding to the b cell edge and the X‐ray structure identified a solvent‐mediated crystal contact adjacent to position Glu81 that was hypothesized to limit efficient crystal growth in this dimension. In this report, a series of mutations at this crystal contact designed to both reduce side‐chain entropy and replace the solvent‐mediated interface with direct side‐chain contacts are reported. The results suggest that improved crystal growth is achieved upon the introduction of direct crystal contacts, while little improvement is observed with side‐chain entropy‐reducing mutations alone.