Crystallographic Snapshots of Functional Motions in Cobalamin Maintenance and Methylphosphonate Production

Abstract

Biochemical experiments provide key insight into the molecular logic and mechanisms underlying the biology surrounding us. Supplementing this biochemistry with detailed molecular models helps confirm, refine, and create hypotheses regarding complex biological systems. This thesis leverages crystallography to contextualize complex biochemical data. In Part I, we fill a major gap in the understanding of chaperone-mediated cobalamin delivery and repair. The molecular snapshots presented open new doors in the study of cobalamin transfer and help explain the molecular basis of human disease. In Part II, a set of crystal structures are used to compare and contrast two related enzymes involved in phosphonate metabolism. A subtle rearrangement in the active site of one enzyme hints at the molecular basis for methylphosphonate metabolism, and this hypothesis is confirmed by structure-guided engineering. Although diverse, both stories showcase the value of atomic resolution in clarifying complex biochemical processes.