In 1941, G. W. Beadle and E. L. Tatum provided the first definitive experimental evidence that individual genes are responsible for directing the synthesis of specific polypeptides. Thirteen years later, in an equally important revelation, C. B. Anfinsen demonstrated that a protein’s three-dimensional structure is determined solely by the primary sequence of its composite amino acids. Together, these two discoveries provided the foundation for our modern view of information transfer in biological systems – single genes code for individual polypeptides, and these polypeptides adopt distinct structures that dictate their cellular functions. This central tenet has empowered much of the genetic and biochemical investigations of the last half-century, thereby enabling the elucidation of a multitude of biological pathways and processes.
Recent advances in DNA sequencing and genome biology are ushering in a new era in the biological sciences. The genomic sequences of more than 180 distinct organisms have been completed within the last decade. Contained within these genomes are an estimated 1,000,000 genes, many of which code for proteins with unknown biological functions. Many of these newly uncovered polypeptides could serve as useful targets for the development of novel therapeutics. Unfortunately, the rate of assigning functions to new gene products pales in comparison to the rapidity with which sequence information is added to existing databases. The goal of our research program is to utilize modern techniques in bacterial genetics, molecular biology and protein biochemistry to elucidate the molecular functions of newly discovered gene products. Once identified, these polypeptides are subjected to detailed mechanistic investigations to reveal the fundamental chemical principles that govern their biological activity. Three central questions provide the framework for our scientific explorations – How do proteins catalyze the chemical transformations that are required for life? How do proteins evolve new catalytic activities to overcome biological “bottlenecks”? How do proteins control the nucleation and templated synthesis of inorganic materials? I encourage you to visit our laboratory website for a description of ongoing research projects.
Beck, T, Miller BG (2013) Structural basis for regulation of human glucokinase by glucokinase regulatory protein, Biochemistry ASAP.
Xiao, Q, Jackson, JJ, Basak, A, Bowler, JM, Miller, BG, Zakarian A (2013) Enantioselective synthesis and reinvestigation of the glucokinase activating properties of tatanans A-C, Nature Chem. 5, 410-416.
Bowler, JM, Hervert, KL, Kearley, ML, Miller, BG (2013) Small-molecule allosteric activation of human glucokinase in the absence of glucose, ACS Med. Chem. Lett. 4, 580-584
Larion, M, Salinas, RK, Bruschweiler-Li, L, Miller, BG, Bruschweiler, R (2012) Order-disorder transitions govern kinetic cooperativity and allostery of monomeric human glucokinase, PLoS Biol. 12, e1001452.
Larion, M, Miller, BG (2012) Homotropic allosteric regulation in monomeric mammalian glucokinase, Arch. Biochem. Biophys. 519, 103-111.