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Chris Tate: Thermostabilizing GPCRs for Structural Biology

For most of the 1990s and early 2000s, GPCR structural biology was not a biology problem - it was a stability problem. Receptors that fell apart in any useful detergent could not be crystallized, and without crystals, there were no structures. Chris Tate spent years working on membrane proteins that were simply too unstable to study by crystallography, and the question of how to solve that became the organizing problem of his career.

The answer came from an unexpected source: a paper on thermostabilization of an unrelated membrane protein, read on a Friday afternoon in the library. That insight led to a systematic mutation screen, a 21-degree improvement in receptor thermostability, and eventually the co-founding of Heptares - a company now running over 250 GPCR structures and six clinical candidates.

This conversation covers how thermostabilization changed what was structurally possible, how cryoEM then redrew the map again, and what the first solved Class D GPCR dimer reveals about receptor architecture at its most unexpected.

ABOUT THE GUEST

Chris Tate is a group leader at the MRC Laboratory of Molecular Biology in Cambridge, UK, where his research focuses on the structural and biochemical study of membrane proteins, with particular emphasis on GPCRs. His work developed the thermostabilization platform - a systematic approach to engineering receptor stability for structural biology - that enabled the first high-resolution crystal structures of multiple GPCRs in defined conformational states.

He co-founded Heptares (now Sosei Heptares) in 2007, a company that has since produced over 250 GPCR structures and advanced six candidates into clinical trials. His current structural work extends to Class D GPCRs, including the recently solved first dimer architecture in this receptor family.

SCIENTIFIC THEMES OF THE CONVERSATION

Membrane protein instability as the overlooked bottleneck in GPCR structural biology
The thermostabilization platform - from concept to systematic mutation screen
From academic discovery to co-founding Heptares: decision, funding, and growth
CryoEM and the conformational states that crystallography could never access
Class D GPCR architecture - what a dimer with no prior blueprint looks like
What remains unsolved: why drug discovery still fails in late-stage clinical trials

KEY INSIGHTS FROM THE CONVERSATION

Stability, not biology, was the bottleneck

The reason GPCR structures took so long was not scientific complexity - it was that the receptors destroyed themselves in every detergent needed for crystallography. Tate's work reframed the problem: before asking what a receptor does, you first have to ask whether it can survive the conditions required to study it.

A Friday afternoon and a paper on an unrelated protein

The thermostabilization insight did not come from the lab. It came from Tate's habit of spending Friday afternoons in the library reading outside his immediate field. A 1999 paper on thermostability of diacylglycerol kinase - a protein with no connection to GPCRs - produced a light-bulb recognition that reshaped his entire research direction.

21 degrees changed what was chemically possible

Thermostabilizing the beta-adrenergic receptor by 21 degrees Celsius was not a marginal improvement. It meant the receptor could survive in harsh short-chain detergents that had previously killed it instantly - including SDS. That stability was what made crystallization tractable and what became the foundation of Heptares.

CryoEM opened conformational space that crystallography had locked out

The arrestin-coupled state of a GPCR - a structure that required the agonist-bound receptor to be held in its active conformation - could never have come from crystallography. CryoEM removed that constraint, and Tate argues the field is still at the beginning of what this means: inactive-state structures, full conformational sets, and throughputs that were previously inconceivable.

A Class D GPCR dimer with no prior blueprint

The first solved structure of a Class D GPCR - a yeast receptor from family D - turned out to be a dimer, with an architecture that breaks the rules of class A receptor biology. The dimer interface sits on helix 1, involves a domain-swapped N-terminus and helix 7, is twice the area of the G protein coupling interface, and positions helix 4 over 20 angstroms from where it appears in any known class A receptor. A PhD student solved it in under two years.

Drug discovery's real bottleneck is not structural

Tate is direct about where the field now stands: accumulating GPCR structures is no longer the limiting step in drug discovery. The harder problem is understanding the human body well enough to predict why a compound that works in vitro fails in Phase 2 or Phase 3 - and solving that will require tools and systems that structural biology alone cannot provide.

Science requires a skin like a rhino

Tate's advice to young scientists is not procedural - it is temperamental. Science is brutal, things fail for months, and the only way through is genuine passion for being in the lab. He still asks every candidate who wants to join his group one question: do you know, in chemical terms, how a miniprep kit works? The answer reveals whether someone is curious about science or merely using it.

EPISODE TIMELINE

Timestamps are AI-generated from the transcript and may vary slightly from the final edited audio.

01:35 Meet Tate - membrane protein biochemist, MRC LMB
02:12 Career origin: from calcium ATPase to bacterial transporters
13:52 Path into GPCRs - instability as the bottleneck nobody was solving
17:00 The Friday afternoon library paper that changed GPCR structural biology
24:21 Thermostabilizing the beta receptor by 21 degrees - in any detergent, including SDS
25:56 Co-founding Heptares - the canteen conversation and the venture capital meeting
32:02 Raising £21M during the 2009 financial crisis
37:43 The cryoEM revolution - why the arrestin-coupled structure could never have come from a crystal
45:17 Unpublished: a Class D GPCR dimer - one PhD student, 18 months, a Nature paper
49:05 Advice for young scientists: what it actually takes to survive science
54:35 The curiosity test: do you know how your miniprep kit works?
58:34 Three aha moments - a diffraction pattern, a thermostabilization screen, and a synchrotron

SELECTED QUOTES

"None of my best ideas have ever arisen from being in the lab. Never. Because when you're in the lab, you're thinking about what's in front of you."

"I don't think ever in my life I will ever write an application and just produce so much more than what I wrote in the original application."

"Science is brutal. It is absolutely brutal. Things don't work for months. You have to be robust, you have to have a skin like a rhino sometimes."

"When you see the GPCR field, all you see is this accelerating number of structures and information, and that is just going to get faster and faster. And I think that is now the minor part."

About this episode

Dr. Chris Tate obtained his Ph.D. from the University of Bristol in 1989 and then moved to the University of Cambridge (Dept. of Biochemistry) to work on bacterial sugar transporters. After obtaining a research fellowship at Girton College (Cambridge) he moved to the LMB in 1992 to work in Richard Henderson's group on the serotonin transporter. Chris also worked on the E. coli multidrug transporter EmrE and obtained both 2D and 3D crystals as well as a 3D structure using cryo-EM.

In 2005 he started working on the development of conformational thermostabilization of GPCRs, which resulted in the structure of the β1-adrenoceptor. Subsequent work has focused on understanding the molecular basis of GPCR pharmacology through structure determination of the β1-adrenoceptor and adenosine A2A receptor in multiple different conformations bound to ligands of different efficacy.

In 2016 mini-G proteins were developed as a tool for the structure determination of GPCRs in the fully active state. Structures have been determined by X-ray crystallography of receptors coupled to either mini-Gs or mini-Go, and also by electron cryo-microscopy of receptors coupled to mini G protein bound to βγ subunits. Recent work includes the first structure determination of a GPCR bound to a biased agonist and coupled to arrestin and also the first structure of a Class D receptor.

Join me to learn more about Chris’s work and his role in founding Heptares which was later acquired by Sosei and became Sosei Heptares.

Dr. Chris Tate on the web