8etp

From Proteopedia

Cryo-EM structure of cGMP bound closed state of human CNGA3/CNGB3 channel in GDN

Structural highlights

8etp is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.52Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

CNGB3_HUMAN Stargardt disease;Progressive cone dystrophy;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 Visual signal transduction is mediated by a G-protein coupled cascade using cGMP as second messenger. This protein can be activated by cGMP which leads to an opening of the cation channel and thereby causing a depolarization of rod photoreceptors. Induced a flickering channel gating, weakened the outward rectification in the presence of extracellular calcium, increased sensitivity for L-cis diltiazem and enhanced the cAMP efficiency of the channel when coexpressed with CNGA3 (By similarity). Essential for the generation of light-evoked electrical responses in the red-, green- and blue sensitive cones.^[1]

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^[2]

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
↑ 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