Happy to share molecular mechanics of AMPA-subtype ionotropic glutamate receptor (iGluR) pre-activation and complete gating pathway revealed by time-resolved cryo-EM with the help of full and partial agonists. www.nature.com/articles/s41... youtu.be/Uc0Bo2N9puU

Complete gating, including pre-activation, of AMPA-subtype iGluR – Sobolevsky Lab

YouTube video by Sobolevsky Lab

youtu.be

AMPA receptor gating proceeds through an intermediate pre-active state that has structurally remained an enigma. We used cryo-EM as well as full and partial agonists to resolve this state and for the first time structurally reveal the complete gating pathway of AMPARs. www.nature.com/articles/s41...

Happy to share the results of our study of structural and functional regulation of GluA2 AMPA receptor by inhibitory auxiliary subunits GSG1L and TARP gamma5 and by epilepsy-associated disease mutations. www.nature.com/articles/s41...

Here is a highlight of our work on TRPV1 agonist MSP20, which binds to the vanilloid site, desensitizes TRPV1, and shows the potential of a long-lasting analgesic with neuroprotective effects. cryosparc.com/blog/trpv1-m...

The Pain Paradox: Activating TRPV1 to Silence Its Response | CryoSPARC

Combining rational drug design, functional studies, and cryo-EM, researchers characterize a selective TRPV1 agonist that promotes desensitization and prolonged pain relief.

cryosparc.com

Officially published! A new TRPV1 agonist MSP20, which binds to the vanilloid site and desensitizes TRPV1. Our structural and preclinical studies highlight the potential of MSP20 as a long-lasting analgesic with neuroprotective effects. www.nature.com/articles/s41...

Officially published! Structures of TRPV3 with Olmsted syndrome mutations, which reduce channel’s temperature sensitivity, uncover the molecular basis of this severe genodermatosis and highlight unique features of TRPV3 channel gating. www.nature.com/articles/s41...

Officially published! Structurally characterized five Olmsted syndrome mutants, which have reduced temperature sensitivity and destabilized non-conducting states, highlighting unique features of TRPV3 channel gating and guiding new therapeutic strategies. www.nature.com/articles/s41...

Happy to report a new TRPV1 agonist MSP20, which binds to the vanilloid site, desensitizes TRPV1 and suppresses pain signaling for extended time. Our structural and preclinical studies highlight MSP20 as a potential long-lasting analgesic with neuroprotective effects. www.nature.com/articles/s41...

We used cryo-EM to characterize five TRPV3 mutants causing severe genodermatosis Olmsted syndrome (OS). Our results highlight conserved TRP channel gating mechanisms, uncover the molecular basis of OS and provide a guide for future therapeutic strategies. www.nature.com/articles/s41...

Mutations in TRP channel TRPV3 cause severe genodermatosis called Olmsted syndrome (OS). We used cryo-EM to characterize five OS mutants, which exhibit reduced temperature sensitivity and disrupt structural elements stabilizing non-conducting states of TRPV3. www.nature.com/articles/s41...

Mechanism of human TRP channel TRPV6 block by polyamine spermine (SPM). The main binding site of SPM is in the selectivity filter of TRPV6. Amazing collaboration with Chubanov and Efremov labs. www.nature.com/articles/s41...

As of May 28, this article has been made open access. I apologize for any inconvenience caused earlier. I was uncertain at the time of publication whether I could cover the open access fee. www.nature.com/articles/s41...

Mechanism of conductance control and neurosteroid binding in NMDA receptors - Nature

Ion-channel conductance levels are controlled by the bending patterns of pore-forming transmembrane helices in the heterotetrameric neuronal channel GluN1a-2B N-methyl-D-aspartate receptor.

nature.com

Happy to share the stepwise mechanism of human TRP channel TRPV6 block by polyamine spermine. Intracellular spermine makes two transient stops in the channel pore before binding to the main site in the selectivity filter. Collaboration with Chubanov and Efremov groups. www.nature.com/articles/s41...

Happy to share the stepwise mechanism of human TRP channel TRPV6 block by polyamine spermine. Intracellular spermine makes two transient stops in the channel pore before binding to the main site in the selectivity filter. Collaboration with Chubanov and Efremov groups. www.nature.com/articles/s41...

The KHL's Gagarin Cup is apparently pretty heavy, Lokomotiv G Alexei Melnichuk needed a spotter here 😂

Officially out in Nature Communications: Auxiliary subunits reshape heterotetrameric GluA1/A2 AMPA receptor core! Structures of the most abundant AMPA receptor di-heteromer in the brain GluA1/A2 in the closed, open, and desensitized states! www.nature.com/articles/s41...

Auxiliary subunits reshape structural asymmetry and functional plasticity in heterotetrameric GluA1/A2 AMPA receptor core - Nature Communications

Native AMPA receptors are heteromeric complexes of GluA1-4 and auxiliary subunits. Here, authors report structures of the most abundant GluA1/A2 core in the closed, open, and desensitized states, allo...

nature.com

Officially out in Nature Communications: Auxiliary subunits reshape heterotetrameric GluA1/A2 AMPA receptor core! Structures of the most abundant AMPA receptor di-heteromer in the brain GluA1/A2 in the closed, open, and desensitized states! www.nature.com/articles/s41...

Hot out of the press: Auxiliary subunits reshape structural asymmetry and functional plasticity in heterotetrameric GluA1/A2 AMPA receptor core! Structures of the most abundant AMPA receptor di-heteromer GluA1/A2 in the closed, open, and desensitized states! www.nature.com/articles/s41...

I've written a review on what I think is an extremely exciting direction in cryo-EM: Cryo-EM of endogenous membrane proteins in their native lipid bilayer Open access in Quarterly Reviews of Biophysics: doi.org/10.1017/S003...

Claudin 24—A novel enhancer of AMPA receptor fidelity | Science Advances www.science.org/doi/10.1126/...

Claudin 24—A novel enhancer of AMPA receptor fidelity

The claudin subfamily family member Cldn24 is identified as an AMPAR auxiliary subunit.

science.org

Happy to share new review of endothelium glutamate receptors in brain pathology. www.frontiersin.org/journals/pha...

Oligonucleotide (ON) RGLS4326 designed for treatment of ADPKD caused CNS-related toxicity due to competitive antagonism of AMPA receptors. Understanding this allowed making a new ON devoid of toxicity. Collaboration with Regulus/Novartis! @LauraYen42 @MariaKarela3 www.nature.com/articles/s41...

Discovery of new AMPA receptor regulators – RNA molecules that act as competitive antagonists causing CNS-related toxicity when intended for treatment of autosomal dominant polycystic kidney disease (ADPKD). Collaboration with Regulus Therapeutic/Novartis! www.nature.com/articles/s41...

Oligonucleotide (ON) RGLS4326 designed for treatment of ADPKD caused CNS-related toxicity due to competitive antagonism of AMPA receptors. Understanding this allowed making a new ON devoid of toxicity. Collaboration with Regulus/Novartis! @LauraYen42 @MariaKarela3 www.nature.com/articles/s41...

Now in the journal issue! Structures of kainate receptor GluK2 in the closed apo state and open conducting state bound to agonist kainate and positive allosteric modulator BPAM. www.nature.com/articles/s41...

Now in the journal issue! Molecular mechanism of activation of kainate receptor GluK2 in complex with auxiliary subunit Neto2. www.nature.com/articles/s41...

Magnesium site in human oncochannel TRPV6 is formed by two negatively charged residues that are close together in the closed state and separated in the open state. Mg2+ binding keeps these residues together and stabilizes the closed state. With Chubanov/Efremov labs! www.nature.com/articles/s41...

Magnesium site in TRPV6 is formed by two negatively charged residues that are close together in the closed state and separated in the open. Magnesium binding keeps them together and stabilizes the closed state. Amazing collaboration with Chubanov and Efremov groups. www.nature.com/articles/s41...

Magnesium site in TRPV6 is formed by two negatively charged residues that are close together in the closed state and separated in the open. Magnesium binding keeps them together and stabilizes the closed state. Amazing collaboration with Chubanov and Efremov groups. www.nature.com/articles/s41...

Happy to share the locking mechanism of human oncochannel TRPV6 inhibition by intracellular magnesium. Amazing collaboration with Chubanov and Efremov groups. www.nature.com/articles/s41...