Scientific Abstract

G protein-coupled receptors (GPCRs) remain one of the most important classes of drug targets in modern pharmacology. In this conversation, Dr. Joseph Kim discusses the intersection of structural biology, membrane protein biochemistry, and drug discovery through the lens of GPCR research.

Dr. Kim, a postdoctoral scholar in the laboratory of Dr. Aashish Manglik at the University of California, San Francisco, studies GPCR structure using cryo-electron microscopy. His work focuses on understanding how ligands interact with receptors such as the μ-opioid and κ-opioid receptors, and how structural insights can guide the development of new pharmacological modulators.

The discussion explores how structural biology technologies—particularly cryo-EM—have transformed the ability to visualize receptor-ligand interactions and uncover the molecular mechanisms underlying receptor signaling. Dr. Kim also reflects on the conceptual challenges of studying membrane proteins, the value of pursuing difficult scientific problems, and how curiosity about drug mechanisms led him toward GPCR pharmacology.

Listeners will gain insight into the scientific reasoning behind GPCR structural studies, the evolving toolkit used to interrogate receptor activation, and the broader landscape of receptor-based drug discovery.

About the Guest

Dr. Joseph Kim is a structural biologist studying membrane proteins and GPCR pharmacology. He is currently a postdoctoral scholar in the laboratory of Dr. Ashish Manglik at the University of California, San Francisco, where he uses cryo-electron microscopy to investigate ligand binding and receptor conformations.

Dr. Kim’s research focuses on druggable membrane proteins, particularly GPCRs involved in neurological signaling such as opioid receptors and the galanin receptor family. His work combines structural biology, membrane protein biochemistry, and pharmacological insights to better understand how ligands modulate receptor signaling.

His broader scientific interests lie at the interface of structural biology and drug discovery, where molecular structures inform the design and development of new therapeutics.

Scientific Themes of the Conversation

• Structural biology of GPCR–ligand interactions

• Cryo-electron microscopy in membrane protein research

• GPCR pharmacology and drug discovery strategies

• Opioid receptor structure and ligand modulation

• Challenges in targeting peptide-binding GPCRs

• Exploring understudied receptors such as the galanin receptor family

Key Insights from the Conversation

1. Difficult Scientific Problems Often Drive Discovery

Dr. Kim describes a personal inclination toward challenging research areas. Membrane proteins—historically difficult to purify and structurally characterize—represent precisely the kind of problems that attract scientists interested in pushing methodological boundaries.

2. Structural Biology Reveals the Molecular Logic of Drug Action

Through cryo-EM studies of the μ- and κ-opioid receptors, Dr. Kim explains how visualizing receptor-ligand complexes provides direct insight into how small molecules stabilize specific receptor states and produce pharmacological effects.

3. GPCR Drug Discovery Is Increasingly Structural

Modern GPCR drug discovery increasingly integrates structural data, computational docking, and pharmacology. Structural snapshots of receptor-ligand complexes can validate docking predictions and guide medicinal chemistry.

4. Polypharmacology Is a Central Challenge

One small molecule studied by Dr. Kim’s group interacts with multiple opioid receptors, acting as an antagonist at one receptor and an inverse agonist at another. This illustrates how receptor pharmacology often involves complex, receptor-specific effects.

5. Many GPCRs Remain Poorly Understood

The galanin receptor family represents an example of GPCRs with important physiological roles but limited pharmacological tools. The lack of potent small-molecule ligands continues to hinder research into these receptors.

6. New Tools Enable Re-exploring Old Questions

Advances in cryo-EM, computational modeling, and machine learning are enabling scientists to revisit receptors that were previously considered difficult to drug.

7. Scientific Environments Matter

Dr. Kim emphasizes the importance of research environments that allow curiosity, experimentation, and even failure. Supportive collaborative environments accelerate scientific progress.

Episode Timeline

00:00 — Introduction

Introduction to Dr. Joseph Kim and his current position at UCSF.

01:00 — Early curiosity about drugs and poisons

How childhood curiosity about toxic plants led to an interest in drug research.

05:00 — Choosing science over medicine

Transition from a pre-medical track to pursuing scientific research.

07:00 — Discovering cryo-electron microscopy

Graduate training in cryo-EM and early exposure to membrane protein structural biology.

10:00 — Pursuing challenging scientific problems

Why difficult fields like membrane protein structural biology can be particularly appealing.

18:00 — Choosing a postdoctoral lab

Criteria used to identify the right postdoctoral environment.

23:00 — The scientific appeal of membrane proteins

How membrane proteins serve as the entry point for signaling molecules.

29:00 — Structural studies of opioid receptors

Dr. Kim describes solving structures of μ- and κ-opioid receptors bound to small-molecule ligands.

34:00 — The galanin receptor: an understudied GPCR

Why the galanin receptor family presents intriguing scientific questions.

45:00 — Scientific turning points

Three key “aha moments” that shaped Dr. Kim’s scientific trajectory.

52:00 — Advice for young scientistsThe importance of curiosity, persistence, and choosing supportive research environments.

Selected Quotes

Full Transcript

(Formatted for readability. Minor transcription artifacts removed while preserving scientific meaning.)

Dr. Yamina Berchiche:

Hello, everyone. This is Yamina from Dr. GPCR. I'm very excited to be recording this particular podcast episode. Joe reached out to me on LinkedIn, and we started a fantastic conversation, and I'm excited to bring you, Joe, to the podcast today. Joe Kim, welcome to the Dr. GPCR podcast.

Dr. Joseph Kim:

Thank you, Yamina. It's an absolute pleasure to be here.

Dr. Yamina Berchiche:

Very excited to have you on. Maybe we can start by you introducing yourself to the audience.

Dr. Joseph Kim:

My name is Joseph Kim. I go by Joe. I am currently a postdoctoral scholar in Professor Ashish Manglik’s lab here at the University of California, San Francisco.

Dr. Yamina Berchiche:

Wonderful. I’m going to put it out there on the record—I’ve been reaching out to Ashish. We're going to have to push him towards coming onto the podcast. I listened to one of his talks at a Gordon Conference and he was phenomenal.

Ashish, if you’re listening to this—we want you on the podcast.

So Joe, tell me a little bit about how you ended up working on GPCRs in Ashish’s lab. I’m really curious about your career trajectory.

Dr. Joseph Kim:

Sure. When it comes to how I got involved in GPCRs, I guess I can start from when I was a kid.

I grew up in Corvallis, Oregon, which is a college town about 90 miles south of Portland. There were a lot of trees and outdoor flora and fauna around me. I spent a lot of time exploring and going to the library.

One day I found a book about poisonous plants—essentially explaining which berries you could eat and which you absolutely shouldn’t. That’s probably where my interest in drugs and toxins began.

There’s that saying that the difference between drugs and poisons is often just the dose. That fascination stuck with me.

Later, during my final year of graduate school at UW–Madison, I was thinking about postdoctoral positions and reading papers about drug discovery. I remember distinctly sitting back one day and thinking:

“Ah crud… I’m going to have to study GPCRs, aren’t I?”

And that realization eventually led me to Ashish’s lab.

Dr. Yamina Berchiche:

How did you initially decide to pursue science?

Dr. Joseph Kim:

I was always interested in science growing up, especially health sciences.

When I started college at Oregon State University, I entered as a pre-med student. But I realized something about myself—I would spend too much time asking why certain treatments were prescribed.

That constant questioning felt more aligned with being a scientist than being a physician.

Dr. Yamina Berchiche:

You mentioned earlier that the project you worked on involved the μ-opioid receptor and the κ-opioid receptor with a small molecule that showed interesting pharmacology. What happened to that project? Was it eventually published?

Dr. Joseph Kim:

Yes, it was published this year in ACS Central Science.

Dr. Yamina Berchiche:

Congratulations—that’s wonderful.

All right, I always ask this question from everyone who comes on the podcast. What is your favorite GPCR?

Dr. Joseph Kim:

People will probably assume that it’s one of the opioid receptors, but I’m actually going to surprise them.

My favorite GPCR is not the opioid receptors. Instead, it’s the galanin receptor.

Dr. Yamina Berchiche:

The galanin receptor? I’m not very familiar with that one.

Dr. Joseph Kim:

Exactly—and that’s part of why I find it so fascinating.

There are three members of the galanin receptor family: galanin receptor 1, 2, and 3. The one I’m most interested in is galanin receptor 1. It’s highly expressed in the brain and spinal cord.

There’s evidence suggesting that it plays roles in feeding behavior and analgesia, somewhat similar to opioid receptors. Some studies also suggest that the galanin receptors may interact with the μ-opioid receptor. In fact, some groups believe there may even be dimeric interactions between the receptors.

But the major challenge is that no one has identified a potent small-molecule ligand for these receptors.

Dr. Yamina Berchiche:

That’s fascinating.

Dr. Joseph Kim:

Recently, structures of galanin receptors bound to their endogenous peptide ligand—galanin—were published.

Those structures revealed something really unusual: the peptide binds laterally within the receptor. That unusual binding mode might explain why it has been so difficult to identify small-molecule ligands.

Dr. Yamina Berchiche:

That makes sense. Whenever I hear about peptide-binding GPCRs with buried or hydrophobic binding pockets, I immediately think: good luck finding small molecules.

Dr. Joseph Kim:

Exactly. The endogenous peptide is buried laterally within the receptor, which means an exogenous small molecule might have difficulty accessing that pocket.

Dr. Yamina Berchiche:

Unless you start thinking about allosteric modulators.

Dr. Joseph Kim:

Right—and once you start thinking about allosteric modulation, you open an

entirely new set of questions.

Dr. Yamina Berchiche:

Absolutely. Especially when you consider that the galanin system involves three receptors and potentially different signaling pathways.

I just looked it up while we were talking. It appears galanin has roles in nociception, depression, and sleep.

That’s a complicated pharmacological landscape.

Dr. Joseph Kim:

It is. You could easily imagine separate therapeutic programs targeting those different physiological effects.

And of course, that also means the pharmacology becomes much more complex.

Dr. Yamina Berchiche:

So how did you first encounter the galanin receptor?

Dr. Joseph Kim:

It actually came from discussions with Ashish when I first joined the lab.

I told him I was interested in three things:• structural biology• drug discovery• neurological systems

The galanin receptor fit all three of those interests.

So Ashish introduced it as a potential project area, and it stuck with me.

Dr. Yamina Berchiche:What kinds of questions are you hoping to answer about that receptor family?

Dr. Joseph Kim:

At a very basic level, one of the key questions is simply:

Can we identify a small molecule that modulates the galanin receptor?

In the early 2000s there were screening campaigns against these receptors, but nothing promising emerged.

So the question becomes:

Did we simply not search deeply enough?Or were the screening strategies themselves limited?

With today’s tools—computational docking, structural biology, and machine learning—we might be able to revisit those questions in a more sophisticated way.

Dr. Yamina Berchiche:

I completely agree.

We now have tools that simply didn’t exist ten or twenty years ago. That means receptors that were previously considered difficult or unproductive targets might be worth revisiting.

But I also think we need to use these tools carefully.

Dr. Joseph Kim:

Yes, exactly.

One of the risks with new technologies is that people sometimes build the research question around the tool rather than using the tool to answer the question.

We need to integrate these tools thoughtfully rather than simply following the excitement.

Dr. Yamina Berchiche:

I agree.

There are really two complementary directions in GPCR research.

One direction is to develop new tools using well-characterized receptors—the ones we understand well enough to validate new methods.

The other direction is to apply those tools to the more challenging or understudied receptors.

Dr. Joseph Kim:

Exactly. You need a solid foundation.

If the receptor system and the tool are both unknowns, it becomes very difficult to interpret the results.

Dr. Yamina Berchiche:

That’s a great point.

Let’s shift gears a little bit.

Looking back at your career so far, what would you say are the three biggest “aha moments” that shaped your trajectory as a scientist?

Dr. Joseph Kim:

The first one was definitely the moment I described earlier—when I was sitting there reading papers and suddenly realized:

“I’m going to have to study GPCRs.”

That was a turning point.

The second “aha moment” came when I solved the structures of the μ-opioid and κ-opioid receptors bound to the candidate small molecule we were studying.

Showing those structures to my colleagues—and realizing that the experiment actually worked—was incredibly satisfying.

It also helped me overcome the fear I had about transitioning into membrane protein structural biology.

The third “aha moment” happened much earlier, when I switched from the pre-med track to pursuing graduate school.

One of my close friends at the time noticed how quickly I pivoted once I realized that medicine wasn’t the right path for me.

That moment clarified that research was the direction where I really belonged.

Dr. Yamina Berchiche:

That’s a beautiful chronological sequence.

If we think about your future—have you started thinking about what comes after your postdoctoral work?

Dr. Joseph Kim:

Yes, I have.

I would like to remain in drug discovery, ideally working on GPCRs if possible.

I can imagine myself in a biotech or pharmaceutical environment where I’m helping guide drug development programs—evaluating data from different teams and deciding whether a candidate molecule should move forward.

That might involve integrating information from pharmacology, toxicology, manufacturing, and preclinical research.

Essentially serving as a bridge between the science and the development process.

Dr. Yamina Berchiche:

That sounds like an exciting direction.

And finally, what advice would you give to young scientists who want to enter the GPCR field?

Dr. Joseph Kim:

The first piece of advice is don’t let fear stop you.

It’s completely normal to feel intimidated when entering a complex field like GPCR biology.

But that fear shouldn’t prevent you from pursuing ideas that excite you.

The second piece of advice is to find an environment where you are allowed to learn from mistakes.

The reason I was able to transition successfully into GPCR structural biology was because I joined a lab where people were supportive and willing to teach.

Being in that kind of environment makes a huge difference.

Dr. Yamina Berchiche:

I completely agree.

The worst thing you can do in science is nothing. Taking action—even if it leads to mistakes—helps you learn and move forward.

Joe, thank you so much for joining the podcast today. I really enjoyed our conversation.

Dr. Joseph Kim:

Thank you, Yamina. It’s been an absolute pleasure.

Dr. Yamina Berchiche:

Thank you.