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Summary

 

Dr Paul Miller - Group leader

University lecturer


E-Mail:
Tel: +44 (0) 1223 361267 / Lab: 334177

 

Keywords

Protein engineering, protein-protein interactions, GABAA receptors, Cys-loop receptors, pLGICs, nanobodies, X-ray crystallography, cryo-EM, electrophysiology

Investigator biography

Paul did his PhD and a postdoc with Professor Trevor G Smart at University College London, where he applied electrophysiological and pharmacological approaches to link structure and function for, principally, glycine receptors. Subsequently, from 2010, Paul attained a Wellcome Trust OXION postdoctoral fellowship, in the Division of Structural Biology at University of Oxford, where he played an important role in establishing methodologies for structural studies of membrane proteins within the department. Paul used these techniques to solve structures of GABAARs and, through collaboration, was involved in raising immunological modulators against GABAARs with novel pharmacology and high selectivity. He joined the Department of Pharmacology, University of Cambridge as a lecturer in 2018.

Research summary

Small molecule agonists, modulators and inhibitors of ion channels are essential pharmacological tools in almost all aspects of neuroscience research. Selectivity between channel types, especially subtypes with high sequence identity in a druggable pocket, presents a key limitation. In contrast, immunological agents can exhibit supreme specificity and therefore selectivity for a single ion channel subtype. Traditionally however, immunological agents have been utilized in passive binding roles to “label” ion channels, rather than as pharmacological tools, i.e. as agonists, modulators and inhibitors. This is a huge missed opportunity for the field of neuropharmacology. The development of such antibodies will reveal fundamental insights into the molecular underpinnings of neurological function and propel the advancement of therapeutics for central nervous system (CNS) disorders. Necessary for this are improvements in CNS antibody delivery. My research aims to progress the development of antibody drug tools and complementary delivery systems, in order to address these shortcomings.

 

Key publications

Heteromeric GABAA receptor structures in positively-modulated active states.

Miller. PS, Masiulis. S, Malinauskas T, Kotecha. A, Rao. S, Chavali. S, De Colibus. L, Pardon. E, Hannan. S, Scott. S, Sun. Z, Frenz. B, Klesse. G, Li. S, Diprose. DM, Siebert. AC, Esnouf. RM, DiMaio. F, Tucker. SJ, Smart. TG, Steyaert. J, Babu. MM, Sansom. MSP, Huiskonen. JT, Aricescu. AR.

https://www.biorxiv.org/content/early/2018/06/05/338343

 

Structural basis for GABAA receptor potentiation by neurosteroids.

Miller. PS, Scott. S, Masiulis. S, De Colibus. L, Pardon. E, Steyaert. J, Aricescu. AR.

Nature Structure and Molecular Biology. 2017, 24(11), p. 986-992.

 

Structural basis of Smoothened regulation by its extracellular domains.

Byrne. EFX, Sircar. R, Miller. PS, Hedger. G, Luchetti. G, Nachtergaele. S, Tully. MD, Mydock-McGrane. L, Covey. DF, Rambo. RP, Sansom. MSP, Newstead. S, Rohatgi. R, Siebold. C.

Nature. 2016, 535, p. 517-522.

 

Crystal structure of a human GABAAR.

Miller. PS, Aricescu. AR.

Nature. 2014, 512, p. 270-275.

 

Cys-loop Receptors: Activation and Modulation.

Miller. PS, Smart TG.

Trends in Pharmacological Sciences. 2010, 31, 4, p.161.