This episode examines a cryo-EM study that resolves the human sweet taste receptor (TAS1R2+TAS1R3) bound to two artificial sweeteners, revealing how a single receptor recognizes diverse sweet compounds and couples to G proteins.
0:00Welcome to Base by Base, the papercast that brings genomics to you wherever you are. Thanks for listening, and don't forget to follow and rate us in your podcast app. So uh, picture this for a second. Yeah. You are holding an ice cold can of regular soda.
0:13Oh, yeah. The classic sugary stuff. Right, exactly. You pot the tab. You take a sip and your tongue is instantly flooded with natural sugar. Now imagine putting that down and picking up a diet soda. You take a sip of that one.
0:25And this time, there is absolutely 0 sugar in the can. Yeah, zero. It is sweetened entirely by a lab made chemical. Yet in both scenarios, your brain registers the exact same deeply satisfying, you know, unmistakable sensation of sweetness.
0:43It's actually a phenomenal biological illusion when you really think about it, because artificial sweeteners, things like sucalose and aspartame. They are completely different chemically from natural sugar.
0:54Right, they don't look anything alike under a microscope. Exactly. They don't share the same molecular rings or atomic structures at all. And furthermore, they are hundreds, sometimes 1000s of times more potent by weight.
1:05Yeah. Yet somehow, these entirely foreign molecules managed to hijack the exact same biological hardware in our mouths. So that's the big question, right? How does our body map completely different chemical shapes into the exact same irresistible taste?
1:21Like what really happens at a microscopic level when a 0 calorie molecule hits your tongue? That is exactly what we're getting into today. Yeah, to figure this out, we are taking a deep dive into a recent, really breakthrough structural biology paper.
1:34Our mission today is to uncover the atomic secrets of the human sweet receptor. Which is, it's just a fascinating mechanism. It really is. We want to see physically how it acts as a universal translator for all things sweet, and to explore how visualizing this process could fundamentally change the future of the food we eat.
1:52And, uh, before we get too deep into the weeds, today we celebrate the work of Zheng Wen, Zheng Yuan Lu, Charles Zuker, and the research team at Columbia University's Zuckerman Institute, as well as the Howard Hughes Medical Institute, who have advanced our understanding of the human sweet taste receptor.
2:09Absolutely. So let's rewind a bit to set the stage. Over 20 years ago, researchers 1st identified the Mammalian Sweet Taste Receptor. Right, the hardware itself. Yeah. And I've always thought of this receptor as an incredibly versatile lock, because usually in biology, a lock has one specific key, right?
2:28A certain hormone fits perfectly into a certain receptor and, you know, nothing else does. Right. very exclusive. But this sweet receptor is a lock that can be picked by wildly different keys. You have natural sugars like glucose and fructose, you have artificial sweeteners, de amino acids, and even certain intensely sweet proteins found in tropical fruits.
2:49Oh, yeah, like fomatin. Exactly. And they all managed to pick this exact same lock. That extreme versatility is really one of the 2 defining characteristics of this receptor system. The lock itself is what we call a heterodimer.
3:02A heterodimer. Okay, break that down for us. So that means it's a single functional unit, but it's built out of 2 distinct protein subunits sitting side by side. They are known as TS1R2 and TS1R3. TS1R2 and TS1R3.
3:17Right. And if you are missing either one of them, the entire system fails, they are an obligatory pair. Okay, so I'm assuming that versatility is the 1st characteristic of the system. What makes up the 2nd part of the puzzle?
3:29The 2nd part is its affinity, or rather, its lack thereof. This receptor evolved to have a surprisingly low affinity for natural sugars. Low affinity. Yeah. In biochemical terms, it requires a millimaolar concentration of sugar to actually activate the receptor. Okay.
3:46To put that simply, it takes a massive amount of the molecule to trigger a response compared to most other biological sensors in our bodies. Wait, wait. If sugar is literal, metabolic energy like, the core fuel that kept our ancestors alive, shouldn't our bodies be hypersensitive to it?
4:02You would think so, right? Yeah. If you have a sensor for something vital, you usually want it to be highly tuned. Why would having a low affinity receptor, one that is essentially hard of hearing when it comes to sugar, be an evolutionary advantage?
4:16It seems completely counterintuitive until you look at it from a foraging perspective. A low affinity receptor is actually an evolutionary superpower. Really? Yeah. Imagine if your sweet receptors were highly sensitive.
4:28The moment you took a bite of, say, a slightly sweet piece of celery or a bland root. Your receptors would be fully saturated. The biological signal would peak instantly. Oh, I see the problem. It would be like a volume knob on a stereo that jumps from 0 to 100 the 2nd you touch it.
4:44Exactly. If the volume is already maxed out by a piece of celery. Then when you stumble across a highly caloric honeycomb, it wouldn't taste any sweeter. You would lose the ability to differentiate. You've hit on the exact mechanism.
4:57By requiring a massive amount of sugar to fully activate, this low affinity receptor prevents our taste buds from maxing out on trace amounts of carbohydrate. Gives you a wider range. Right. It gives our sensory system a wide dynamic range.
5:11This allows animals to constantly seek out, compare, and differentiate between the most energy rich, dense food sources available. You always want the capacity to recognize a bigger, better, more caloric prize.
5:23That makes total sense. So, because this receptor is so vital to our survival. And because it has this bizarre ability to recognize so many different shapes, scientists have desperately wanted to see its 3D structure, right?
5:36Oh, for decades, yeah. Because if we can see the lock, we can understand how all these different keys turn it. But mapping a complex membrane protein is notoriously difficult. It is a nightmare for structural biologists.
5:48I can imagine. These proteins live embedded in the greasy, fatty lipid bylayer of the cell. So I guess when you try to pull them out of that fatty membrane into a watery test tube to study them, they essentially just fall apart.
6:01They absolutely do. Membrane proteins are highly unstable outside their natural environment. The portions of the protein that touch the fat of the cell membrane are hydrophobic, meaning they repel water.
6:12When exposed to a watery laboratory solution, they clump together or lose their shape entirely. So to finally get a picture of this receptor, the researchers had to rely on a methodology called single particle, cryo electron microscopy, or cryo EM.
6:27Cryo-E-M. I mean, that has revolutionized biology over the last decade. It is basically taking a molecular flash photograph isn't it? That is the perfect way to visualize the process. Instead of trying to force the proteins to form a rigid crystal, which, by the way, membrane proteins hate doing, you take your purified protein, put it on a microscopic grid, and plunge it into liquid ethane at staggering speeds.
6:51Wow. It happens so quickly that the water molecules don't even have time to arrange themselves into ice crystals. They freeze instantly into a glass like state called vitreous ice. Which traps the proteins in their exact natural physical shape without crushing them.
7:05Exactly. Then you shoot a beam of electrons through this glassy ice and capture 1000s of 2D images from different angles. Like a super high-tech CT scan. Yeah, and using immense computational power, you reconstruct a 3D image at an atomic level.
7:19In this study, they achieved resolutions down to 3.3 to 4.4 angstroms. Just to put that scale in perspective for you, listening. Yeah. And Istrom is 110 billionth of a meter. It's unimaginably small. We are talking about mapping individual amino acid side chains and atomic bonds, but knowing how finicky membrane proteins are, just getting the functional task one R2 and task one R3 pair onto that grid must have been a massive hurdle.
7:46It was a monumental challenge. When the team tried to purify the receptor. Instead of getting that necessary functional pair of task one R2 and task one R3, the proteins misbehaved. How so? They found that task one R2 subunits kept pairing up with other cast one R2 subunits, they were stubbornly forming non-functional homodimers.
8:05Oh, I see. I think of it like trying to photograph a pair of ballroom dancers. Okay, I like that You need to capture the lead and the partner to understand the walls. The moment you bring them into the studio, the leads keep wandering off to dance with other leads.
8:16You end up with 2 people trying to lead a waltz, which doesn't work, and you completely lose the actual dynamic of the real partnership you're trying to study. That's a great analogy. In a living cell, there is an entire suite of biological machinery chaperoned proteins and cellular membranes that ensures they pair up correctly.
8:34But in an isolated test tube, TAS1R2's hydrophobic regions cause it to self associate. So how do you fix that? If they keep self-asssociating, I'm guessing you have to physically tether them to something else so they behave.
8:48That is the core of their solution. They tether them together by hijacking the cell's own internal messaging system. The sweet receptor belongs to a massive family called G protein coupled receptors, or GPCRs.
9:00These receptors work by binding to a specific G protein on the inside of the cell to send their signal downstream. So the researchers took a stabilizing version of this G protein called mini discuss and fused it directly to the end of the TS one or 3 subunit.
9:15Wait, so because this G protein naturally wants to interact with the entire assembled receptor complex, attaching it permanently to the TS1R3 subunit means it acts like a molecular pair of handcuffs. Exactly.
9:28It mechanically drags the TS103 subunit into a stable complex with TS1 or two. That is so clever. But does tying them together like that alter the natural shape of the lock? That is always the concern in structural biology.
9:41You don't want to introduce artifacts. So, to ensure the complex remained intact, and in its true biological shape, they purified the receptors in the presence of stabilizing agents. They used a polymer called peg 400.
9:55Peg 400. You can think of PEG 400 as a synthetic chemical shield that mimics the fatty environment of the cell membrane, keeping the proteins comfortable and preventing them from unfolding. And most importantly, they use the artificial sweeteners themselves, sucralose, and aspartame, to lock the receptor into its active bound confirmation.
10:13Okay, so after flash freezing them with these chemical shields and molecular handcuffs, they finally get the snapshot. What does the molecular dance actually look like? The architecture is stunning. The defining feature of this specific family of class C GPCRs is a massive structure that sits on the outside of the cell, extending into the saliva.
10:31By all just call this the Venus flytrap domain. Venus fly trap. I assume that's because it literally looks and acts like the carnivorous plant. Like, it has 2 lobes with a cleft in the middle that snaps shut when something lands inside it.
10:43That visual is remarkably accurate. Both taste one R2 and taste one R3 have their own distinct Venus flytrap domain. Okay. But the big reveal, the fascinating finding from this structural map is a stark asymmetry in how they function.
10:55Asymmetry. Yeah. When you look at the 3D map, the taste one R2 subunit is doing all the heavy lifting. Its Venus flytrap domain is the one that physically binds the sweetener, snap and shut around the molecule.
11:08Oh, wow. Furthermore, on the inside of the cell, it is the taste one R2 subunit that actually couples to the G protein to initiate the chemical signal to the brain. Before we go further, we should probably clarify a key term here for the listener.
11:20When we talk about the sweetener molecule, the sugar, or the aspartane that actually lands in the trap. We're referring to the ligand. Yes, the legend. So if I understand correctly, the licend is only being caught by one side of this partnership.
11:34Yes. Tase one or 2 binds the legend and triggers the internal signal. If taste one R2 is catching the ligand and sending the signal, what is taste one R3 doing? Is it just, like, strructural scaffolding along for the ride?
11:47It might seem that way at 1st glance, but without taste one or three, the system is completely broken. Really? Yeah. Well, the Tate one or 2 trap clamps down on the legend. The Venus Flytrap domain of Taste 103 remains in an open confirmation.
12:02It doesn't bind the sweetener at all. However, it acts as an obligatory structural anchor. Without Tice 103 maintaining that specific open posture and supporting the architecture. The entire receptor cannot assemble properly in the cell membrane.
12:15And more importantly, it cannot undergo the necessary mechanical shift required to push against the inner cell machinery and activate the G protein. So it is the ultimate supporting act. It doesn't get the glory of catching the ligand, but the show literally does not happen without it.
12:29Exactly. And the researchers didn't just capture this in an image, though. They actually went into the genetics to prove it. Right. This is where the atomic resolution really pays dividends. Because they could see the exact pocket in TAS1 R2, where the ligan sits, they identified the specific amino acids lining that pocket.
12:49Which ones? We are talking about microscopic residues like Tyrecene 103, aspartic acid 142, and Serene 165. Basically, these are the specific atomic hooks and grooves that reach out and grab the sugar molecule.
13:02You got it. So the team went into the genetic code and selectively swapped out those specific amino acids in the TIS one or 2 Venus flight trap domain. See what happened. Exactly. They mutated them to a much simpler amino acid called alanine, which essentially removes the chemical hook without destroying the overall shape of the protein.
13:21Right, like a dummy replacement. Yeah. And when they did that and tested the receptor, its response to both sucralose and natural sucrose was completely abolished. The lock was broken. You filed down the pins inside the Tumblr and the key couldn't turn it anymore.
13:35That's a perfect way to put it. But what strikes me is the shared architecture of this space. It is profound. They mapped the receptor bound to sucralose, and then they map a separate structure bound to aspartame.
13:47And those are very different. Completely different. Aspartame and sucralose are chemically distinct from each other. Sucralose is a modified sugar molecule with chlorine atoms attached, while aspartame is a dipeptide, essentially 2 amino acids linked together.
14:02Both are vastly different from a natural sugar molecule like glucose, yet both of these synthetic artificial sweeteners wedge themselves into this exact same microscopic pocket on TAS1R2. They trigger the exact same Venus fly trap to clamp shut.
14:19That answers the core question we started with. That is physically why a diet soda tastes exactly the same as a regular soda. Precisely. Even though the molecules floating around in the liquid look absolutely nothing alike under a microscope, they both manage to perfectly trigger that single, highly specific Venus fly trap on the TS1 or 2 subunit.
14:38And once that trap snaps shut, The mechanical force is transferred across the membrane, and the electrical signal sent down your nerve to your brain is identical, sweetness detected. It highlights the incredible functional versatility of that specific binding pocket.
14:53It evolved 1000000s of years ago to bind massive amounts of natural sugar, but it just so happens to possess the perfect geometry to bind these completely modern synthetic molecules with incredibly high affinity.
15:07It's wild. But if we zoom out and connect this atomic reality to the broader natural world, it raises a really interesting question. What that? Well, if this TS1 or 2 pocket is the universal mammalian suite receptor, why do different animals respond so differently to sweets?
15:23Oh, this is a fun topic? Because, I mean, I can offer my dog a piece of fruit and he loves it, but if I offer it to my cat, she couldn't care less. And what about like laboratory mice? This structural map beautifully explains those evolutionary quirks.
15:35Because those specific amino acids in the binding pocket dictate exactly what fits and what tastes sweet. Tiny genetic differences across species have profound behavioral effects. Give us an example. So, humans and apes can easily taste the sweetness of aspartame, but rodents and New World monkeys cannot.
15:53Really? They can't taste it at all. Not at all. Over evolutionary time, a few microscopic changes occurred in the amino acids lining their TA1R2 pocket. Because of those tiny shifts, the aspartane molecules simply doesn't fit into the mouse receptor.
16:09Wow. To a mouse, a packet of aspartam is completely tasteless. So we have a multi-billion dollar artificial sweetener industry built entirely around a molecule that a mouse wouldn't cross the street for.
16:21Exactly. That is amazing. But what about my cat ignoring the fruit? Cats represent an extreme example of evolutionary specialization. Over 1000000s of years, animals with highly specialized diets stopped encountering sugar in their natural environments.
16:34Right. Cats are obligate carnivores. their diet consists entirely of meat. Yes. Another great example is vampire bats, which exclusively drink blood. In evolutionary biology, there is a strict rule. If you don't use it you lose it.
16:47Because maintaining biological hardware that you don't use is a waste of metabolic energy. Precisely. Over 1000000s of years, random mutations naturally accumulated in the taste one or 2 genes of these animals.
17:00For an animal that relies on fruit, a broken sweet receptor would be a death sentence, and that mutation would be weeded out by natural selection. But because sugar wasn't necessary for the survival of cats or vampire bats, those broken jeans were just passed down.
17:14Today, their tests one or 2 genes are completely broken pseudo genes. They have entirely lost the biological ability to build the test one or 2 protein. So my cat isn't just being aloof when I offer her a marshmallow.
17:28She literally lacks the physical hardware to perceive it. She physically cannot paste it. It just tastes like textured air to her. Her sensory world is entirely devoid of the concept of sweet. It's a completely different way of experiencing food.
17:42So translating this back to our daily lives, having this atomic level map of the functional human suite receptor represents a massive paradigm shift for food science and the beverage industry, doesn't it?
17:52Oh, absolutely. It changes everything. Because historically, the discovery of artificial sweeteners has relied heavily on trial and error. Often, it's just accidental discoveries in a lab. Much of our history with sweeteners is pure serendipity.
18:06A chemist synthesizes a random compound, accidentally licks their finger, and discovers its sweet. Which is terrible lab safety, by the way. Very true. But from there, companies might synthesize 1000s of slightly altered compounds and physically taste test them to see what works best.
18:21It is a slow, inefficient process. But now, by knowing the exact topography of the human suite receptor, the precise angles, distances, and electrical charges of the amino acids in the Thai S1R2 pocket food scientists can move to rational design.
18:37So instead of trying 1000000s of random keys in the dark, you essentially take a microscopic mold of the lock and custom 3D print the perfect key to fit it. That is exactly what rational design is. They can rationally design an entirely new generation of taste modulators and non-coloric sweeteners.
18:53They can model molecules on a computer that perfectly fit the TS1R2 pocket. That's incredible. Crucially, this atomic map could help engineers eliminate the downsides of current sweeteners. Many people experience a bitter aftertaste with diet sodas.
19:07Oh yeah. That metallic taste. Right. With rational design, they can craft molecules that only perfectly activate the sweet receptor trap, while completely avoiding any cross-reactivity with the bitter receptors on the tongue.
19:21That is a game changer for anyone who avoids diet drinks because of that lingering aftertaste. But looking at the scope of this paper, we should also acknowledge the limitations of the current study. We don't have the complete start to finish picture of sweet paste yet, do we?
19:36It is a monumental 1st step. But it remains incomplete. The researchers currently only have the active sweetener bound structure of their receptor. Using your previous analogy, they essentially have a high resolution picture of the Venus Fly trap only after it has snapped shut around the sugar molecule. Future research needs to capture the apo state.
19:56The apostate, meaning the inactive unbound state of the receptor before the sugar arrives. Because to really understand how a complex machine works, you need to see the mechanism in both its resting and active states.
20:08We absolutely need the apo state to fully understand the mechanical shift, the physical torque that happens the exact millisecond. A sugar molecule hits the tub. Furthermore, because of the massive challenges with stabilizing the complex, we still need a complete picture of the full receptor firmly bound to the natural interacellular signaling complex, not just the tethered mini G protein they used as a workaround here.
20:31Right the handcuffs. Yeah. There is still much more to learn about how the mechanical force of that Venus flytrap closing is transmitted down through the cell membrane to fire the nerve. Well, to summarize the central insight cleanly.
20:43The human sweet taste receptor is a biological marvel. It relies entirely on the TS102 subunit to catch diverse, sweet molecules like a baseball glove, while its silent partner, TS1R3, anchors the entire system, allowing the trap to snap shut.
20:59It's an elegant system. It really is. This single, highly adaptable structure drives our universal human attraction to natural sugar. And wonderfully. It explains how wildly different artificial chemicals can wedge themselves into the same pocket, tricking our brains into experiencing the exact same pleasure.
21:18And it leaves us with a fascinating new question for you to think about. What does this mean for the future of our diets as we learn to perfectly engineer molecules that satisfy our evolutionary cravings without the metabolic calories?
21:31This episode was based on an open access article under the CCBY 4.0 license. You can find a direct link to the paper and the license in our episode description. If you enjoy this, follow or subscribe in your podcast app and leave a 5 star rating.
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