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-Structure paper
| タイトル | Mechanisms underlying modulation of human GlyRα3 by Zn and pH. |
|---|---|
| ジャーナル・号・ページ | Sci Adv, Vol. 10, Issue 51, Page eadr5920, Year 2024 |
| 掲載日 | 2024年12月20日 |
著者 | Kayla Kindig / Eric Gibbs / David Seiferth / Philip C Biggin / Sudha Chakrapani / ![]() |
| PubMed 要旨 | Glycine receptors (GlyRs) regulate motor control and pain processing in the central nervous system through inhibitory synaptic signaling. The subtype GlyRα3 expressed in nociceptive sensory neurons ...Glycine receptors (GlyRs) regulate motor control and pain processing in the central nervous system through inhibitory synaptic signaling. The subtype GlyRα3 expressed in nociceptive sensory neurons of the spinal dorsal horn is a key regulator of physiological pain perception. Disruption of spinal glycinergic inhibition is associated with chronic inflammatory pain states, making GlyRα3 an attractive target for pain treatment. GlyRα3 activity is modulated by numerous endogenous and exogenous ligands that consequently affect pain sensitization. To understand the mechanism of two such endogenous modulators, Zn and protons, we have used cryo-electron microscopy to determine structures of full-length human GlyRα3 in various functional states. Whereas acidic pH reduces peak glycine response, Zn displays biphasic modulation in a concentration-dependent manner. Our findings reveal the effector sites and also capture intermediate conformations in the gating cycle. Combined with molecular dynamics simulations and electrophysiology, this work provides important insights into GlyRα3 activation and regulation. |
リンク | Sci Adv / PubMed:39693447 / PubMed Central |
| 手法 | EM (単粒子) |
| 解像度 | 2.19 - 3.07 Å |
| 構造データ | EMDB-44899, PDB-9bu2: EMDB-44900, PDB-9bu3: EMDB-44933, PDB-9bvh: EMDB-44934, PDB-9bvj: EMDB-44963, PDB-9bwb: EMDB-44964, PDB-9bwc: EMDB-44970, PDB-9bwe: EMDB-44974, PDB-9bwg: EMDB-44976, PDB-9bwj: EMDB-45073, PDB-9bzp: |
| 化合物 | ![]() ChemComp-GLY: ![]() ChemComp-PIO: ![]() ChemComp-PX4: ![]() ChemComp-HOH: ![]() ChemComp-CLR: ![]() ChemComp-ZN: |
| 由来 |
|
キーワード | MEMBRANE PROTEIN / Glycine / Ion Channel / Ligand-Gated / Pentameric |
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