GPCRs in VR: Psychedelic! Structure of LSD bound to human serotonin receptor

Nanome

6 May 202114:34

EducationalLearning

32 Likes 10 Comments

TLDRIn this video, a team of researchers, including a PhD student named Asher, explores the molecular interactions of psychedelics with serotonin receptors. They discuss LSD's structure and its binding to the 5-HT2B receptor, highlighting the diethylamide group's crucial role in its potency and long-lasting effects. The study also delves into biased signaling in GPCRs, comparing LSD's effects to common antidepressants and the potential of these compounds in treating mental health issues, especially in the context of the COVID-19 pandemic's impact on society.

Takeaways

🧪 The video discusses the analysis of molecules with a focus on how psychedelics interact with serotonin receptors, a key area of research for the guest, Asher.
🎓 Asher is a PhD student at the University of Saskatchewan, studying the mechanisms of psychedelics within serotonin and cannabinoid receptors.
🔬 The video features a team of experts including a medicinal chemist, a structural biologist, and Asher to explore the effects of small molecules on protein structures.
💊 LSD and psilocybin (the active component in magic mushrooms) are highlighted as molecules of interest due to their structural similarity to serotonin and their potential antidepressant effects.
📈 A study mentioned in the video compared the effectiveness of SSRIs (a common antidepressant) to that of psilocybin, showing that the latter may have longer-lasting effects with less frequent dosing.
🔑 The script explains the importance of the tryptamine scaffold and the diethylamide moiety in LSD's structure for its mechanism of action.
🔍 The video delves into the structural biology aspect, showing the co-crystallized structure of LSD with a serotonin receptor, revealing the basis for LSD's long-lasting effects.
🤔 The concept of biased signaling in GPCR receptors is introduced, explaining how different pathways can lead to intoxicating effects or therapeutic benefits.
🔄 The diethylamide group in LSD is shown to rotate by 60 degrees upon binding, which is a key factor in its potency and the duration of its effects.
🧬 Mutation of a leucine residue to an alanine in the receptor is discussed, demonstrating how it affects the binding and release of LSD, potentially influencing the duration of a 'trip'.
🌐 The video concludes with a hopeful outlook on the role of scientific research in addressing mental health issues, particularly in the context of the COVID-19 pandemic's impact on society.

Q & A

What is the main focus of Asher's research as a PhD student?
-Asher's research focuses on understanding how psychedelics work inside serotonin receptors and cannabinoid receptors, which are the ones that THC and marijuana bind to.
What is the significance of the tryptamine scaffold in the molecules discussed in the script?
-The tryptamine scaffold is significant because it is a common structural feature in both LSD and serotonin, allowing them to bind to the same GPCR protein receptor.
What is the role of the diathelamide moiety in LSD's mechanism of action?
-The diathelamide moiety in LSD is critical for its mechanism of action, as it rotates when binding to the receptor, which is a key driver for LSD's potency and its long-lasting effects.
What is the relevance of biased signaling in GPCR receptors?
-Biased signaling in GPCR receptors is relevant because it can lead to different cellular responses depending on the pathway activated, such as beta arrestin signaling leading to intoxication or the cyclic AMP/G-protein pathway being more therapeutic and less intoxicating.
How does the structure of LSD in the serotonin receptor reveal the basis for its long-lasting effects?
-The structure of LSD bound to the serotonin receptor shows that LSD gets trapped by a 'lid' due to a leucine residue, which makes it difficult for LSD to dissociate from the receptor, thus explaining its long-lasting effects.
What was the outcome of the study comparing the effectiveness of SSRIs to psilocybin for antidepressant use?
-The study found that people felt less depressed taking psilocybin from magic mushrooms once every three weeks compared to taking SSRIs every day, after a six-week study period.
What is the significance of the mutation of leucine to alanine in the receptor's binding pocket?
-Mutating leucine to alanine in the receptor's binding pocket provides more room for LSD to escape, which experimentally resulted in LSD being released from the receptor four times faster than with leucine.
How does the rotation of the diethylamide moiety by 60 degrees contribute to LSD's potency?
-The 60-degree rotation of the diethylamide moiety upon binding contributes to LSD's potency by facilitating strong beta arrestin recruitment, which is associated with the drug's strong psychoactive effects.
What is the difference between the SSAZ and RRAZ enantiomers in terms of their interaction with the receptor?
-The SSAZ enantiomer, with methyl groups pointing in the same direction as the diethylamide moiety, is more potent and recruits beta arrestin similarly to LSD, while the RRAZ enantiomer, with methyl groups pointing in opposite directions, is less potent.
Why is the compound LSA less potent in recruiting beta arrestin compared to LSD?
-LSA is less potent in recruiting beta arrestin because it lacks the diethylamide group, which is crucial for the conformational change that drives strong beta arrestin recruitment and thus LSD's potency.
What is the broader hope for the scientific community's research on these compounds?
-The broader hope is that the scientific community's research on these compounds can lead to advancements in treating mental health issues, including those exacerbated by the COVID-19 pandemic and lockdown measures.

Outlines

00:00

🔬 Introduction to Serotonin and LSD Research

The script begins with a warm welcome to a series focused on GPCRs and VR, featuring a special guest, Asher, who introduces himself as a PhD student at the University of Saskatchewan. His research delves into the workings of psychedelics within serotonin receptors, specifically looking at how they interact with cannabinoid receptors, which are the binding sites for THC and marijuana. The video aims to explore the structural biology of these interactions with the help of a medicinal chemist, Carla, and a structural biologist, Daniel. The script introduces the molecules of interest, including LSD, natural serotonin, and silosen, highlighting their structural similarities and the presence of the tryptamine scaffold, which is critical for their mechanism of action.

05:00

📚 LSD's Mechanism and Structural Analysis

This paragraph delves into the structural analysis of LSD and its interaction with the serotonin receptor. It discusses the significance of the diethylamide moiety in LSD's mechanism of action, which undergoes a 60-degree rotation upon binding, contributing to its potency. The script describes how LSD gets trapped within the receptor due to a leucine residue, which is believed to be the reason for the long-lasting effects of LSD trips. The paragraph also explores the concept of biased signaling in GPCRs, explaining the difference between beta arrestin signaling, which is typically associated with intoxication, and the cyclic AMP or G-protein pathway, which is more therapeutic and less intoxicating. The script also mentions a study comparing the effectiveness of SSRIs to cylosin and psilocybin in treating depression, highlighting the potential of psychedelics in therapeutic applications.

10:01

🧬 Stereoselectivity and the Impact on LSD Potency

The final paragraph focuses on the stereoselectivity of LSD and its derivatives, exploring how the positioning of methyl groups in relation to the diethylamide moiety affects the molecule's ability to recruit beta arrestins and its overall potency. The script introduces two enantiomers, SSAZ and RRAZ, and discusses how their different orientations impact beta arrestin recruitment and the molecule's potency. The use of a compound called LSA, which lacks the diethylamide group, is also discussed, showing a significant drop in potency and beta arrestin recruitment. The paragraph concludes with a reflection on the potential therapeutic applications of these compounds, especially in the context of the mental health challenges posed by the COVID-19 pandemic, and expresses hope for scientific advancements in addressing these issues.

Mindmap

Keywords

💡GPCRs

GPCRs, or G-protein coupled receptors, are a large family of membrane receptors that play a key role in cellular signaling. They are involved in a variety of physiological functions, including sensory perception and neurotransmission. In the video, GPCRs are central to the discussion as they are the receptors that LSD and serotonin bind to, highlighting their importance in the study of psychedelics and their effects.

💡Psychedelics

Psychedelics are a class of hallucinogenic substances that can induce altered states of consciousness and perception. In the script, the focus is on how psychedelics like LSD work inside serotonin receptors, which is a significant aspect of the research presented in the video and contributes to the broader understanding of their therapeutic potential.

💡Serotonin Receptors

Serotonin receptors are a group of GPCRs that respond to the neurotransmitter serotonin. They are involved in controlling mood, anxiety, and other functions. In the video, the guest researcher specializes in studying these receptors and their interaction with psychedelics, which is crucial for understanding the mechanisms behind the mood-altering effects of substances like LSD.

💡Cannabinoid Receptors

Cannabinoid receptors are another type of GPCR that are activated by compounds found in cannabis, such as THC. They are involved in various physiological processes, including pain, mood, and appetite regulation. The script mentions these receptors as part of the researcher's interest, indicating the broad scope of study on how different psychoactive substances interact with the brain's receptors.

💡LSD

LSD, or lysergic acid diethylamide, is a well-known psychedelic drug known for its potent effects on perception and cognition. The video script discusses LSD's molecular structure and its binding to serotonin receptors, emphasizing the importance of understanding its mechanism of action for potential therapeutic applications.

💡Tryptamine Scaffold

The tryptamine scaffold is a chemical structure common to many psychedelic compounds, including LSD and serotonin. The script mentions this scaffold as a critical component of the molecules being studied, suggesting its role in the binding and activity of these substances at their respective receptors.

💡Diethylamide Moiety

The diethylamide moiety is a specific part of the LSD molecule that is highlighted in the script as being critical for its mechanism of action. It is noted for its ability to rotate upon binding to the receptor, which is suggested to contribute to LSD's potency and long-lasting effects.

💡Biased Signaling

Biased signaling refers to the phenomenon where different ligands can activate a GPCR in distinct ways, leading to different cellular responses. The script discusses this concept in the context of GPCRs like the serotonin receptor, explaining how certain compounds, like LSD, can selectively activate certain signaling pathways over others.

💡Beta Arrestin

Beta arrestin is a protein involved in GPCR signaling that can be recruited by certain ligands, leading to specific cellular responses. In the video, beta arrestin signaling is associated with intoxicating effects of compounds like cannabinoids, whereas the absence of this recruitment in LSD is linked to its unique mechanism of action.

💡SSRIs

SSRIs, or selective serotonin reuptake inhibitors, are a class of antidepressant medications that work by increasing the availability of serotonin in the brain. The script contrasts the effects of SSRIs with those of cyclosin, the active component in magic mushrooms, in the context of a study comparing their effectiveness as antidepressants.

💡Structural Biology

Structural biology is the study of the three-dimensional structures of biological macromolecules and how these structures relate to function. In the video, Daniel is there to analyze the structural biology aspect, which is crucial for understanding the detailed interactions between molecules like LSD and their target receptors.

Highlights

Introduction of guest Asher, a PhD student at the University of Saskatchewan, focusing on how psychedelics work inside serotonin receptors.

Asher's research interest in serotonin and cannabinoid receptors, which are involved in the action of THC and marijuana.

The presence of LSD, natural serotonin, and silosen in the discussion, highlighting their similar structures and binding to the same GPCR.

The importance of the tryptamine scaffold in the structure of LSD and its significance for its mechanism of action.

The discussion of a study comparing the effectiveness of SSRIs to psilocybin and magic mushrooms for antidepressant effects.

The revelation of the first picture of a psychedelic drug, LSD, in action with a serotonin receptor, explaining its long-lasting effects.

The concept of biased signaling with GPCR receptors and its implications for intoxicating effects versus therapeutic uses.

The potency of psychedelics as variable antagonists, with LSD having a potency of 0.093 nanomolar.

The role of the diathetamide moiety in LSD's binding and its critical rotation for receptor interaction and beta arrestin recruitment.

The experimental mutation of leucine to alanine to demonstrate how LSD escapes the receptor and the impact on trip duration.

The exploration of the 5-HT2B receptor structure and how LSD remains bound within the binding pocket.

The significance of the 60-degree rotation of LSD's diethylamide moiety for its potency and beta arrestin recruitment.

The use of derivatives SSAZ and RRAZ to demonstrate the impact of stereoselectivity on beta arrestin recruitment and potency.

The comparison of LSD with LSA, which lacks the diethylamide group, showing weaker beta arrestin recruitment and reduced potency.

The discussion on the stereoselectivity of the diethylamide group and its critical role in LSD's action as a psychedelic.

The hope for scientific advancements in mental health treatments, especially in the context of the COVID-19 pandemic's mental health repercussions.

The call for more research into the science of brain chemistry and neurotransmitters for better understanding and treatment of mental health issues.

Transcripts

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GPCRs in VR: Psychedelic! Structure of LSD bound to human serotonin receptor

Takeaways

Q & A

What is the main focus of Asher's research as a PhD student?

What is the significance of the tryptamine scaffold in the molecules discussed in the script?

What is the role of the diathelamide moiety in LSD's mechanism of action?

What is the relevance of biased signaling in GPCR receptors?

How does the structure of LSD in the serotonin receptor reveal the basis for its long-lasting effects?

What was the outcome of the study comparing the effectiveness of SSRIs to psilocybin for antidepressant use?

What is the significance of the mutation of leucine to alanine in the receptor's binding pocket?

How does the rotation of the diethylamide moiety by 60 degrees contribute to LSD's potency?

What is the difference between the SSAZ and RRAZ enantiomers in terms of their interaction with the receptor?

Why is the compound LSA less potent in recruiting beta arrestin compared to LSD?

What is the broader hope for the scientific community's research on these compounds?