Ion channel modulation and antibody/toxin modulator development

Dr Paul Miller

Dr Paul Miller - Group leader

Associate Professor


E-Mail: pm676 [at] cam.ac.uk
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, antibody modulators.

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 established methodologies for the production of membrane proteins within the department. Paul used these techniques to solve structures of GABAARs and for the production of antibodies with novel pharmacology and high selectivity. He joined the Department of Pharmacology, University of Cambridge as a lecturer in 2018 to advance antibody pharmacology of ion channels, and has received funding from AMS, BBSRC, Wellcome, Rosetrees Trust, and a range of industry support.

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

Determining the molecular and physiological actions of subtype-selective nanobodies of GABA-A receptors.

Gonzalez-Prada, J. E., Liu, S., Shang, C., Chernoff, C. S., Bright, D. P., Mortensen, M., Jones, C. J., Nestorow, S. E., Kasaragod, V. B., Chen, W.-N., Hannan, S., Zhou, J., Dunn, A. W. E., Soltani, A., Turner, R. J., Duggan, N. M., Yuan, Y., Wahid, A. A., Hardwick, S. W., Scott, S., Chirgadze, D. Y., Pardon, E., Steyaert, J., Aricescu, A. R., Paulsen, O., Belin, D., Smart, T. G. & Miller, P. S.

Science Advances, 2026, In Press - Coming soon.

Molecular mechanism of action of a blood brain barrier shuttle antibody.

Liu, S., King, O. E., Wahid, A. A., Shang, C., Pattison, L. A., Malinauskas, T., Santander, E. A., Nestorow, S. E., Chen, W.-N., Mavridou, V., Browne, J. I., Smith, E. S. J., Linley, J. E., Webster, C. & Miller, P. S. Preprint on Biorxiv (2026), https://doi.org/10.64898/2026.06.30.735565.

A robust platform for recombinant production of animal venom toxin modulators of ion channels.

Gonzalez-Prada, J.E., Haworth, A., Browne, J., Salvage, S.C., Secomandi, N., Rush, A., Ritoux, A., Dannawi, M., Lee, L., Mavridou, V., Dong, Y.Y., Smith, E.S., Jackson, A., Stevens, E. and Miller P.S.

Pre-print on bioRxiv (2025), doi 10.1101/2025.06.11.659050

https://www.biorxiv.org/content/10.1101/2025.06.11.659050v1.full

The molecular basis of drug selectivity for alpha5 subunit-containing GABAA receptors. 

Kasaragod VB, Malinauskas T, Wahid AA, Lengyel J, Knoflach F, Hardwick SW, Jones CF, Chen W-N, Lucas X, Omari K, Chirgadze DY, Aricescu AR, Cecere G, Hernandez M-C, Miller PS. Nature Structure and Molecular Biology, 2023, Dec, 30(12), p. 1936-1946. PMID: 37903907. 
https://www.nature.com/articles/s41594-023-01133-1

HIGHLIGHTS:

1) Engineered GABA-A a5 receptor for drug design

2) Basis of a5 selectivity for b-carbolines, benzodiazepines and isoxazoles revealed

3) Ligands displacements oberved between isoxazole negative vs positive modulators

Mechanisms of inhibition and activation of extrasynaptic alpha-beta GABAA receptors.

Vikram B. Kasaragod, Martin Mortensen, Steven W. Hardwick, Ayla A. Wahid, Valentina Dorovykh, Dimitri Y. Chirgadze, Trevor G. Smart, Paul S. Miller. Nature, 2022, Feb, 602(7897), p. 529-533. PMID: 35140402. https://www.nature.com/articles/s41586-022-04402-z

HIGHLIGHTS:

1) GABA-A receptor bound by alpha-Cobratoxin

2) Molecular mechanism of inhibition by zinc

3) Observation of a low efficacy GABA-bound conformation

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. Biorxiv, 2018. 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.

Funding

Research in the lab is funded by:

  • AstraZeneca
  • Leverhulme Trust
  • UKRI Medical Research Council
  • UKRI Biotechnology and Biological Sciences Research Council
  • Isaac Newton Trust