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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

I am interested in developing novel pharmacological approaches to control central nervous system (CNS) activity. My focus to date has been on a family of proteins called g–aminobutyric acid type-A receptors (GABAARs). These ligand-gated ion channels are the principal mediators of inhibitory neurotransmission throughout the central nervous system. They reside at synapses and respond to the release of the neurotransmitter GABA to open an intrinsic chloride channel and pass this electrical response into the post-synaptic neuron. Ordinarily they sculpt neuronal relay by regulating excitation and so moderating CNS activity. In conditions where GABAAR signalling is deficient, neurological disorders arise, such as epilepsy, anxiety and insomnia, all linked to over-excitability. Positive allosteric modulators (PAMs) of GABAARs, such as benzodiazepines, boost GABAAR signalling to treat these conditions. Regulating CNS activity by targeting GABAAR signalling is also linked to other conditions including stroke, autism, pain and schizophrenia.

There are many subtypes of GABAARs and the roles of each in brain function and neurological disorders are far from understood. Superior pharmacological agents are required to discriminate between the subtype roles as part of basic biological research and to develop next-generation therapeutics. My research is aimed at developing strategies to overcome the bottleneck in delivery of selective modulators, and closely relies on biochemical, biotechnological, engineering and electrophysiological approaches. These include: structural biology (X-ray crystallography and cryo-EM) for rational ligand design; dye sensors for ligand screening; raising of protein modulators from immunological libraries; testing of modulators in recombinant and neuronal cell systems; engineering of protein modulators for in vivo delivery across the blood brain barrier into the CNS to enable animal behaviour studies. Progress in these areas will allow scientists to control much more precisely specific types of GABAAR signalling in order to probe basic biology and empower therapeutic design.

 

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.