Structural highlights
Disease
CNGB3_HUMAN Progressive cone dystrophy;Stargardt disease;Achromatopsia. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry.
Function
CNGB3_HUMAN Pore-forming subunit of the cone cyclic nucleotide-gated channel. Mediates cone photoresponses at bright light converting transient changes in intracellular cGMP levels into electrical signals. In the dark, cGMP levels are high and keep the channel open enabling a steady inward current carried by Na(+) and Ca(2+) ions that leads to membrane depolarization and neurotransmitter release from synaptic terminals. Upon photon absorption cGMP levels decline leading to channel closure and membrane hyperpolarization that ultimately slows neurotransmitter release and signals the presence of light, the end point of the phototransduction cascade. Conducts cGMP- and cAMP-gated ion currents, with permeability for monovalent and divalent cations.[1] [2] [3] [4]
Publication Abstract from PubMed
Cyclic nucleotide-gated (CNG) channels transduce chemical signals into electrical signals in sensory receptors and neurons. They are activated by cGMP or cAMP, which bind to the cyclic nucleotide-binding domain (CNBD) to open a gate located 50-60 A away in the central cavity. Structures of closed and open vertebrate CNG channels have been solved, but the conformational landscape of this allosteric gating remains to be elucidated and enriched. Here, we report structures of the cGMP-activated human cone photoreceptor CNGA3/CNGB3 channel in closed, intermediate, pre-open and open states in detergent or lipid nanodisc, all with fully bound cGMP. The pre-open and open states are obtained only in the lipid nanodisc, suggesting a critical role of lipids in tuning the energetic landscape of CNGA3/CNGB3 activation. The different states exhibit subunit-unique, incremental and distinct conformational rearrangements that originate in the CNBD, propagate through the gating ring to the transmembrane domain, and gradually open the S6 cavity gate. Our work illustrates a spatial conformational-change wave of allosteric gating of a vertebrate CNG channel by its natural ligand and provides an expanded framework for studying CNG properties and channelopathy.
Conformational trajectory of allosteric gating of the human cone photoreceptor cyclic nucleotide-gated channel.,Hu Z, Zheng X, Yang J Nat Commun. 2023 Jul 18;14(1):4284. doi: 10.1038/s41467-023-39971-8. PMID:37463923[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Sundin OH, Yang JM, Li Y, Zhu D, Hurd JN, Mitchell TN, Silva ED, Maumenee IH. Genetic basis of total colourblindness among the Pingelapese islanders. Nat Genet. 2000 Jul;25(3):289-93. PMID:10888875 doi:http://dx.doi.org/10.1038/77162
- ↑ Peng C, Rich ED, Varnum MD. Achromatopsia-associated mutation in the human cone photoreceptor cyclic nucleotide-gated channel CNGB3 subunit alters the ligand sensitivity and pore properties of heteromeric channels. J Biol Chem. 2003 Sep 5;278(36):34533-40. PMID:12815043 doi:10.1074/jbc.M305102200
- ↑ Zheng X, Hu Z, Li H, Yang J. Structure of the human cone photoreceptor cyclic nucleotide-gated channel. Nat Struct Mol Biol. 2022 Jan;29(1):40-46. PMID:34969976 doi:10.1038/s41594-021-00699-y
- ↑ Hu Z, Zheng X, Yang J. Conformational trajectory of allosteric gating of the human cone photoreceptor cyclic nucleotide-gated channel. Nat Commun. 2023 Jul 18;14(1):4284. PMID:37463923 doi:10.1038/s41467-023-39971-8
- ↑ Hu Z, Zheng X, Yang J. Conformational trajectory of allosteric gating of the human cone photoreceptor cyclic nucleotide-gated channel. Nat Commun. 2023 Jul 18;14(1):4284. PMID:37463923 doi:10.1038/s41467-023-39971-8
