I hold a chair at the Newcastle University Biosciences Institute as Professor of Structural Biology. I lead a team of postdoc and graduate researchers in the Yue lab, integrated into the Newcastle Structural Biology Laboratory. My research focuses on a moleulcar understanding towards the cause and therapy for rare metabolic diseases, and aligns with the research theme of Discovery of Medicines of the Faculty of Medical Sciences.
wyatt [dot] yue [at] newcastle [dot] ac [dot] uk
Catherine Cookson Building M3.008, Framlington Place, Newcastle NE2 4HH
Fragment Screening Reveals Starting Points for Rational Design of Galactokinase 1 Inhibitors to Treat Classic Galactosemia
Mackinnon SR, Krojer T, Foster WR, Diaz-Saez L, Tang M, Huber KVM, von Delft F, Lai K, Brennan PE, Arruda Bezerra G, Yue WW
ACS Chem Biol 16, 586-595
Identification of small molecule allosteric modulators of 5,10-methylenetetrahydrofolate reductase (MTHFR) by targeting its unique regulatory domain
Bezerra GA, Holenstein A, Foster WR, Xie B, Hicks KG, Bürer C, Lutz S, Mukherjee A, Sarkar D, Bhattacharya D, Rutter J, Talukdar A, Brown PJ, Luo M, Shi L, Froese DS, Yue WW
Biochimie 183, 100-107
Human aminolevulinate synthase structure reveals a eukaryotic-specific autoinhibitory loop regulating substrate binding and product release
Bailey HJ, Bezerra GA, Marcero JR, Padhi S, Foster WR, Rembeza E, Roy A, Bishop DF, Desnick RJ, Bulusu G, Dailey HA Jr, Yue WW
Nat Commun 11(1), 2813
Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism
Fox NG, Yu X, Feng X, Bailey HJ, Martelli A, Nabhan JF, Strain-Damerell C, Bulawa C, Yue WW, Han S
Nat Commun 10(1), 2210
Palladium-mediated enzyme activation suggests multiphase initiation of glycogenesis
Bilyard MK, Bailey HJ, Raich L, Gafitescu MA, Machida T, Iglésias-Fernández J, Lee SS, Spicer CD, Rovira C, Yue WW, Davis BG
Nature 563, 235-240
ENZYME ASSEMBLIES & COMPLEXES
Many metabolic enzymes performing essential cellular roles function as homo-oligomeric assemblies, or in concert with other partner proteins in the cell. Therefore studying enzymes in the context of their higher order complexes is key to understanding functions. We adopt novel approaches in recombinant co-expression and endogenous isolation of metabolic complexes, for structural, biochemical and biophysical characterisation.
INTEGRATIVE STRUCTURAL BIOLOGY
We combine x-ray crystallography, cryo-electron microscopy and complementary biophysical methods (including differential scanning fluorimetry, surface plasmon resonance, Michaelis-Mention kinetics) to study enzyme structures, dynamics and interactions. We have to date determined > 200 structures, all deposited in the Protein Data Bank. Our goal is to provide insight into functional and disease-causing mechanisms.
SMALL MOLECULE DRUG DISCOVERY
Disease-associated metabolic enzymes often lead to aberrant flux and accumulation of toxic metabolites. Therefore, pathway manipulation to reduce flux to the defective enzyme could have therapeutic benefit. Our objectives are to develop small molecule inhibitors for enzymes upstream of a metabolic defect, as ‘substrate reduction therapy’. Check out our hit discovery projects of GALK1, HAO1, ALAS2 and AASS in the public domain.
Developing small molecule inhibitors for a rare childhood seizure disorder
Action Medical Research and Life Arc
Hit-to-lead development of HAO1 inhibitors of primary hyperoxaluria
Harrington UK Rare Disease Scholar Award
Structural and biophysical characterisation of bicyclic peptides in the context with their therapeutic targets