Year: 2023
Type: article
Abstract: Pain therapy has remained conceptually stagnant since the opioid crisis, which highlighted the dangers of treating pain with opioids. An alternative addiction-free strategy to conventional painkiller-based treatment is targeting receptors at the origin of the pain pathway, such as transient receptor potential (TRP) ion channels. Thus, a founding member of the vanilloid subfamily of TRP channels, TRPV1, represents one of the most sought-after pain therapy targets. The need for selective TRPV1 inhibitors extends beyond pain treatment, to other diseases associated with this channel, including psychiatric disorders. Here we report the cryo-electron microscopy structures of human TRPV1 in the apo state and in complex with the TRPV1-specific nanomolar-affinity analgesic antagonist SB-366791. SB-366791 binds to the vanilloid site and acts as an allosteric hTRPV1 inhibitor. SB-366791 binding site is supported by mutagenesis combined with electrophysiological recordings and can be further explored to design new drugs targeting TRPV1 in disease conditions.
Source: Nature Communications
Language: English
Topic: Ion Channels and Receptors
Subfield: Sensory Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,290
Funders: National Science Foundation, U.S. Department of Energy, U.S. Department of Health and Human Services, Oregon Health and Science University, Frederick National Laboratory for Cancer Research, Deutsche Forschungsgemeinschaft, National Institutes of Health, Office of Science, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Biological and Environmental Research
Awards: G1319434103, Mechanism of Meissner corpuscle function, Molecular mechanism of touch sensitivity in the Schnauzenorgan of the Elephant Nose Fish, G1602829002, G2039066037, G2061904816, G2262290324, NSF/MCB-BSF: Collaborative Research: Towards development of the structural determinants of the Glutamate receptor gating regulation by auxiliary membrane anchored proteins, G2390790659, Entschlüsselung der strukturellen Basis von TRP Kanalinhibierung als Grundlage für neues Medikamentendesign, Molecular mechanisms of the sense of touch, G2771998156, G3388457521, G3508161151, G3804142890, G3823210524, G386607036, Single-Particle Cryo-EM Characterization of AMPA Receptor Functional States, G411694581, G4429615956, Structure and Function of AMPA subtype ionotropic glutamate receptors, G5114759384, G5530725256, G5626970539, G5657290114, G5718375046, G5818665589, Pacific Northwest Center for Cryo-EM, G6221506569, G6372839752, G6414178950, G6414448843, G6743207394, G6780141363, G6848626653, G7562546725, G7673727097, G7913850483, G7986127690, G8149489444, G8461821187, G8775485830, G9000009413, G9000060489, G9000164073, G9000204368, Mechanism of touch sensitivity in rapidly-adapting mechanosensory corpuscles, Structure and Function of Ionotropic Glutamate Receptors, Structure and function of Transient Receptor Potential Channels, Structural and functional principles of activation and regulation of the transient receptor potential channel TRPV3.
OpenAlex ID: W4367312675