Andrija Sente - Research Homepage

Research Interests

Information processing in the brain requires a precise balance between excitation and inhibition in the neuronal microcircuitry. Disturbances to this equilibrium are correlated with several common psychiatric disorders, and many psychoactive substances and therapeutics function by modulating it.

I investigate how this balance is set and maintained at a molecular level through the structural characterization of neurotransmitter receptors and their complexes, as well as through the lens of computational biology. You can read more about my work on GABA_A receptors in my recent essay published in Science, Gatekeepers of the brain: Identifying hidden mechanisms of type A GABA receptor signaling and assembly.

More generally, I am excited by the quest for a better understanding of how the precise wiring of the nervous system is achieved during development, how this patterning is dictated by genetic information, and how and why it goes awry in neurodevelopmental disorders. Most disorders on the neurodevelopmental spectrum are strongly determined by genetics; for example, schizophrenia and autism-spectrum disorder are over 80% genetically determined, yet our ability to interpret this predisposition and vulnerability remains limited. I recently discussed some of these topics in an interview with ScienceAdviser.

Research Preview

Diagram illustrating the differential assembly of GABAA receptors.

Differential assembly of GABA_A receptors (PMID: 35355020).

Cryo-EM structure of the GABAA receptor α1 subunit complexed with the assembly factor NACHO.

Structure of the GABA_A receptor α1 subunit in complex with the assembly factor NACHO (PMID: 39553992).

High-resolution (1.7 Å) Cryo-EM map reconstruction of the GABAA receptor.

GABA_A receptor map reconstructed to 1.7 Å (PMID: 33087931).

Detailed views of the 1.7 Å GABAA receptor map showing ligand coordination, modifications, and hydrogen bonds.

Examples of features visible in the GABA_A receptor map reconstructed to 1.7 Å: ligand coordination in the agonist pocket, post-translational modifications, and hydrogen bond networks (PMID: 33087931).

2D class averages of the GABA_AR α1 subunit - NACHO assembly intermediate (PMID: 39553992).

Publications

A complete and up-to-date list of my publications can be found on my Google Scholar profile.

(* indicates corresponding author, ¹ indicates joint first authors)

2024

Sente A. Gatekeepers of the brain: Identifying hidden mechanisms of type A GABA receptor signaling and assembly. Science. 2024 Nov 15;386(6723):738-9.
Hooda Y¹, Sente A¹, Judy RM¹, Smalinskaitė L, Peak-Chew SY, Naydenova K, Malinauskas T, Hardwick SW, Chirgadze DY, Aricescu AR, Hegde RS. Mechanism of NACHO-mediated assembly of pentameric ligand-gated ion channels. bioRxiv. 2024 Nov 15.

2022

Sente A*, Desai R, Naydenova K, Malinauskas T, Jounaidi Y, Miehling J, Zhou X, Masiulis S, Hardwick SW, Chirgadze DY, Miller KW*, Aricescu AR*, Differential assembly diversifies GABA_A receptor structures and signaling, Nature (2022)
Kleist AB¹, Jenjak S¹, Sente A, Laskowski LJ, Anderson EI, McNally LM, Heukers R, Bobkov V, Peterson FC, Thomas MA, Chevigné A, Smit MJ, McCorvy JD, Babu MM, Volkman BF, Conformational selection guides β-arrestin recruitment at an intrinsically biased G protein-coupled receptor, Science (2022)

2021

Uchański T, Masiulis S, Fischer B, Kalichuk V, López-Sánchez U, Zarkadas E, Weckener M, Sente A, Ward P, Wohlkönig A, Zögg T, Remaut T, Naismith JH, Nury H, Vranken W, Aricescu AR, Pardon E, Steyaert J, Megabodies expand the nanobody toolkit for protein structure determination by single-particle cryo-EM, Nature Methods (2021)

2020

Nakane T¹, Kotecha A¹, Sente A¹, McMullan G, Masiulis S, Brown PMGE, Grigoras IT, Malinauskaite L, Malinauskas T, Miehling J, Yu L, Karia D, Pechnikova EV, de Jong E, Keizer J, Bischoff M, McCormack J, Tiemeijer P, Hardwick SW, Chirgadze DY, Murshudov G, Aricescu AR*, Scheres SHW*, Single-particle cryo-EM at atomic resolution, Nature (2020)

2018

Sente A*, Peer R, Srivastava A, Baidya M, Lesk AM, Balaji S, Shukla AK, Babu MM*, Flock T*, Molecular mechanism of modulating arrestin conformation by GPCR phosphorylation, Nature Struct. Mol. Biol. (2018)

Short Bio

I completed the Medical and Veterinary Science Tripos at the University of Cambridge. During this time, I honed my research skills as a summer student at the MRC Laboratory of Molecular Biology, working on the regulation of G-protein coupled receptor signaling (with M. Madan Babu and Tilman Flock), nucleosome remodelling (with David Barford and Tobias Wauer), and hypoxia sensing (with Mario de Bono and Changchun Chen).

Following the completion of Stage 1 clinical training, I was selected for the Cambridge University Clinical School's MB/PhD program. I conducted my PhD research in Radu Aricescu's group in the MRC LMB's Neurobiology division, where I also stayed for a short post-doc. During this time, I was part of a large academia-industry collaboration that resulted in the first atomic-resolution reconstruction of a biological specimen by cryo-EM. This work was included in the top 10 scientific breakthroughs of 2020 in the annual list compiled by Nature.

My work has been recognized by the British Neuroscience Association's Postgraduate Prize and the Grand Prize of the 2024 Science and SciLifeLab Award for Young Scientists.

Currently, I am a Research Scientist in Machine Learning at InstaDeep Ltd. (a BioNTech company).

Outside of research, I am a musician and sports enthusiast: I love football, chess and hold a black belt in Shotokan karate. I also enjoy books, movies, TV series and spending time in nature.