Lauren Slosky
@laurenslosky.bsky.social
Neuropharmacologist | Assistant Prof at the University of Minnesota | New PI interested in GPCRs, addiction biology & drug discovery | 🔬 ➡️ 🐭
#SfN2025 here we come! I am thrilled to be joined at the Society for Neuroscience meeting this year by Madelyn Moore, @kelseyperson.bsky.social, @valeriarobleto.bsky.social, and Crystal Lemchi. If you are in San Diego for the conference, please stop by to say hi! 👋 🧪🧠🟦
November 14, 2025 at 7:17 PM
#SfN2025 here we come! I am thrilled to be joined at the Society for Neuroscience meeting this year by Madelyn Moore, @kelseyperson.bsky.social, @valeriarobleto.bsky.social, and Crystal Lemchi. If you are in San Diego for the conference, please stop by to say hi! 👋 🧪🧠🟦
These data suggest that G protein selectivity can be tailored with small changes to a single chemical scaffold targeting the GPCR-transducer interface.
October 27, 2025 at 8:50 PM
These data suggest that G protein selectivity can be tailored with small changes to a single chemical scaffold targeting the GPCR-transducer interface.
Differences in the G protein selectivity profiles of these new modulators were probe-independent, conserved across receptor species, and translated to differences in in vivo activity - efficacy in a rodent model of NTSR1 agonist-induced hypothermia.
October 27, 2025 at 8:50 PM
Differences in the G protein selectivity profiles of these new modulators were probe-independent, conserved across receptor species, and translated to differences in in vivo activity - efficacy in a rodent model of NTSR1 agonist-induced hypothermia.
Other compounds produced surprising results indicating that some G protein C-termini can also adopt a third, distinct conformation in the presence of a stabilizing modulator. WHAT. 🤯
October 27, 2025 at 8:50 PM
Other compounds produced surprising results indicating that some G protein C-termini can also adopt a third, distinct conformation in the presence of a stabilizing modulator. WHAT. 🤯
Remarkably, small modifications to the SBI-553 scaffold produce compounds with qualitatively different G protein activation profiles! Some compounds behaved as predicted – like this one 🎳
October 27, 2025 at 8:50 PM
Remarkably, small modifications to the SBI-553 scaffold produce compounds with qualitatively different G protein activation profiles! Some compounds behaved as predicted – like this one 🎳
Can this compound’s G protein selectivity profile be changed by modifying its structure? Yes! Based on these models, we compiled a series of SBI-553 derivatives and screened them in a high-dimensional SAR study including representative G protein family members and β-arrestin.
October 27, 2025 at 8:50 PM
Can this compound’s G protein selectivity profile be changed by modifying its structure? Yes! Based on these models, we compiled a series of SBI-553 derivatives and screened them in a high-dimensional SAR study including representative G protein family members and β-arrestin.
G protein homology models based on this alternative, shallow-binding conformation did a great job at explaining SBI-553’s G protein subtype-specific effects on NT and its own agonism.
October 27, 2025 at 8:50 PM
G protein homology models based on this alternative, shallow-binding conformation did a great job at explaining SBI-553’s G protein subtype-specific effects on NT and its own agonism.
Why does this work? The G protein C-terminus needs to adopt a new binding position to accommodate the compound. SBI-553 blocks G protein binding determinants, promoting association with select G protein subtypes for which a shallow-binding conformation is energetically favorable.
October 27, 2025 at 8:50 PM
Why does this work? The G protein C-terminus needs to adopt a new binding position to accommodate the compound. SBI-553 blocks G protein binding determinants, promoting association with select G protein subtypes for which a shallow-binding conformation is energetically favorable.
If not through β-arrestin, where does the block come from? Subtype-selective steric exclusion. Sensitivity to SBI-553 antagonism is determined by the primary structure of the G protein C-terminus and can be changed by swapping just the 5 C-term amino acids of these G proteins.
October 27, 2025 at 8:50 PM
If not through β-arrestin, where does the block come from? Subtype-selective steric exclusion. Sensitivity to SBI-553 antagonism is determined by the primary structure of the G protein C-terminus and can be changed by swapping just the 5 C-term amino acids of these G proteins.
How does it do this? SBI-553 selectively fully antagonizes NTSR1-Gq/11 coupling. No β-arrestin needed for its G protein antagonism!
October 27, 2025 at 8:50 PM
How does it do this? SBI-553 selectively fully antagonizes NTSR1-Gq/11 coupling. No β-arrestin needed for its G protein antagonism!
This biased allosteric modulator (BAM) biases NTSR1 not only toward β-arrestin, but also toward alternative G protein signaling, switching NTSR1 from a Gq/11 preferring receptor to a G12/13 preferring receptor.
Pretty cool 🧪🧠🟦
Pretty cool 🧪🧠🟦
October 27, 2025 at 8:50 PM
This biased allosteric modulator (BAM) biases NTSR1 not only toward β-arrestin, but also toward alternative G protein signaling, switching NTSR1 from a Gq/11 preferring receptor to a G12/13 preferring receptor.
Pretty cool 🧪🧠🟦
Pretty cool 🧪🧠🟦
When NT and SBI-553 are applied in combination, SBI-553 antagonizes NT-induced activation of some G proteins and promotes NT-induced activation of others. Some strikingly transducer-specific effects here!
October 27, 2025 at 8:50 PM
When NT and SBI-553 are applied in combination, SBI-553 antagonizes NT-induced activation of some G proteins and promotes NT-induced activation of others. Some strikingly transducer-specific effects here!
Interestingly, we found that SBI-553 acts not only as a full β-arrestin agonist at NTSR1 but also a weak G protein agonist for a subset of G proteins (e.g., G12/13, Go).
October 27, 2025 at 8:50 PM
Interestingly, we found that SBI-553 acts not only as a full β-arrestin agonist at NTSR1 but also a weak G protein agonist for a subset of G proteins (e.g., G12/13, Go).
We characterized ligand-directed NTSR1 signaling using a panel of 12 G proteins subtypes and both β-arrestins. While NTSR1’s endogenous ligand NT preferentially activates Gq/11, it also activates nearly all transducers evaluated.
October 27, 2025 at 8:50 PM
We characterized ligand-directed NTSR1 signaling using a panel of 12 G proteins subtypes and both β-arrestins. While NTSR1’s endogenous ligand NT preferentially activates Gq/11, it also activates nearly all transducers evaluated.
How did we get here? A long thread because we've learned a lot!!
We examined the prototypical class A GPCR NTSR1, a receptor for which pathway-specific physiology has been uncovered and an intracellular small molecule allosteric modulator has been identified: SBI-553.
We examined the prototypical class A GPCR NTSR1, a receptor for which pathway-specific physiology has been uncovered and an intracellular small molecule allosteric modulator has been identified: SBI-553.
October 27, 2025 at 8:50 PM
How did we get here? A long thread because we've learned a lot!!
We examined the prototypical class A GPCR NTSR1, a receptor for which pathway-specific physiology has been uncovered and an intracellular small molecule allosteric modulator has been identified: SBI-553.
We examined the prototypical class A GPCR NTSR1, a receptor for which pathway-specific physiology has been uncovered and an intracellular small molecule allosteric modulator has been identified: SBI-553.
These data suggest that G protein selectivity can be tailored with small changes to a single chemical scaffold targeting the GPCR-transducer interface.
October 25, 2025 at 4:06 PM
These data suggest that G protein selectivity can be tailored with small changes to a single chemical scaffold targeting the GPCR-transducer interface.
Differences in the G protein selectivity profiles of these new modulators were probe-independent, conserved across receptor species, and translated to differences in in vivo activity - efficacy in a rodent model of NTSR1 agonist-induced hypothermia.
October 25, 2025 at 4:06 PM
Differences in the G protein selectivity profiles of these new modulators were probe-independent, conserved across receptor species, and translated to differences in in vivo activity - efficacy in a rodent model of NTSR1 agonist-induced hypothermia.
Other compounds produced surprising results indicating that some G protein C-termini can also adopt a third, distinct conformation in the presence of a stabilizing modulator. WHAT.
October 25, 2025 at 4:06 PM
Other compounds produced surprising results indicating that some G protein C-termini can also adopt a third, distinct conformation in the presence of a stabilizing modulator. WHAT.
These data suggest that G protein selectivity can be tailored with small changes to a single chemical scaffold targeting the GPCR-transducer interface.
November 22, 2024 at 4:09 PM
These data suggest that G protein selectivity can be tailored with small changes to a single chemical scaffold targeting the GPCR-transducer interface.
Differences in the G protein selectivity profiles of these new modulators were probe-independent, conserved across receptor species, and translated to differences in in vivo activity - efficacy in a rodent model of NTSR1 agonist-induced hypothermia.
November 22, 2024 at 4:09 PM
Differences in the G protein selectivity profiles of these new modulators were probe-independent, conserved across receptor species, and translated to differences in in vivo activity - efficacy in a rodent model of NTSR1 agonist-induced hypothermia.
Other compounds produced surprising results indicating that some G protein C-termini can also adopt a third, distinct conformation in the presence of a stabilizing modulator🩹. WHAT.
November 22, 2024 at 4:09 PM
Other compounds produced surprising results indicating that some G protein C-termini can also adopt a third, distinct conformation in the presence of a stabilizing modulator🩹. WHAT.
Remarkably, small modifications to the SBI-553 scaffold produce compounds with qualitatively different G protein activation profiles! Some compounds behaved as predicted – like this one🎳.
November 22, 2024 at 4:09 PM
Remarkably, small modifications to the SBI-553 scaffold produce compounds with qualitatively different G protein activation profiles! Some compounds behaved as predicted – like this one🎳.
Can this compound’s G protein selectivity profile be changed by modifying its structure? Yes! Based on these models, we compiled a series of SBI-553 derivatives and screened them in a high-dimensional SAR study including representative G protein family members and β-arrestin.
November 22, 2024 at 4:09 PM
Can this compound’s G protein selectivity profile be changed by modifying its structure? Yes! Based on these models, we compiled a series of SBI-553 derivatives and screened them in a high-dimensional SAR study including representative G protein family members and β-arrestin.
G protein homology models based on this alternative, shallow-binding conformation did an AWESOME job at explaining SBI-553’s G protein subtype-specific effects on NT and its own agonism. 🤯
November 22, 2024 at 4:09 PM
G protein homology models based on this alternative, shallow-binding conformation did an AWESOME job at explaining SBI-553’s G protein subtype-specific effects on NT and its own agonism. 🤯
Why does this work? The G protein C-terminus needs to adopt a new binding position to accommodate the compound. SBI-553 blocks G protein binding determinants, promoting association with select G protein subtypes for which a shallow-binding conformation is energetically favorable.
November 22, 2024 at 4:09 PM
Why does this work? The G protein C-terminus needs to adopt a new binding position to accommodate the compound. SBI-553 blocks G protein binding determinants, promoting association with select G protein subtypes for which a shallow-binding conformation is energetically favorable.