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Molecular Physiology & Biophysics

Derek P. Claxton, PhD

Assistant Professor, Molecular Physiology and Biophysics

Research area: Structural biology and mechanisms of substrate catalysis, transport and inhibition in glucose and lipid metabolism mediated by PAP2 and MFS superfamily membrane proteins

The Claxton laboratory investigates the biochemistry and biophysics of membrane proteins that enable glucose and lipid metabolism. These proteins function as enzymes or transporters, and their dysfunction is linked to metabolic disease. Our primary target is glucose-6-phosphatase, which catalyzes the transport and hydrolysis of the intracellular glucose intermediate glucose-6-phosphate. The function of this multi-component system is critical for hepatic glucose production and fine-tuning glucose-stimulated insulin secretion from pancreatic beta cells. Dysregulation is linked to hyperglycemia in diabetes, and missense mutations that cripple enzyme activity cause glycogen storage disease type 1. Our goal is to define the structural and mechanistic basis of transport and catalysis using an integrated structural biology/biophysics approach that combines the power of computational methods with structure determination (cryoEM, crystallography), EPR spectroscopy and biochemistry. The laboratory has an established collaboration with the O’Brien lab, and is a member of the Center for Structural Biology and the Center for Applied Artificial Intelligence in Protein Dynamics.

Recent publications:

  1. Hawes EM, Rahim M, Haratipour Z, Orun AR, O’Rourke ML, Oeser JK, Kim K, Claxton DP, Blind RD, Young JD, O’Brien RM. Biochemical and metabolic characterization of a G6PC2 inhibitor. Biochimie. 2024 Mar 1;222:109-122. doi: 10.1016/j.biochi.2024.02.012.
  2. Sinclair M, Stein RA, Sheehan JH, Hawes EM, O’Brien RM, Tajkhorshid E, Claxton DP. Integrative analysis of pathogenic variants in glucose-6-phosphatase based on an AlphaFold2 model. PNAS Nexus. 2024 Jan 29;3(2):pgae036. doi: 10.1093/pnasnexus/pgae036.
  3. Hawes EM, Claxton DP, Oeser JK, O’Brien RM. Identification of structural motifs critical for human G6PC2 function informed by sequence analysis and an AlphaFold2-predicted model. Biosci Rep. 2024 Jan 31;44(1):BSR20231851. doi: 10.1042/BSR20231851.
  4. Overway EM, Bosma KJ, Claxton DP, Oeser JK, Singh K, Breidenbach LB, Mchaourab HS, Davis LK, O’Brien RM. Nonsynonymous single-nucleotide polymorphisms in the G6PC2 gene affect protein expression, enzyme activity, and fasting blood glucose. J Biol Chem. 2022 Feb;298(2):101534. doi: 10.1016/j.jbc.2021.101534.
  5. Claxton DP, Overway EM, Oeser JK, O’Brien RM, Mchaourab HS. Biophysical and functional properties of purified glucose-6-phosphatase catalytic subunit 1. J Biol Chem. 2022 Jan;298(1):101520. doi: 10.1016/j.jbc.2021.101520.