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Cryo-EM structure of human ZAC in complex with d-tubocurarine
Structural highlights
FunctionZACN_HUMAN Ligand-gated cation channel that allows the movement of sodium and potassium monoatomic cations across cell membranes when activated by zinc (Zn2+), copper (Cu2+), and changes in pH (PubMed:26872532). Could also transport cesium (PubMed:26872532).[1] B6F2F5_HE71 Acts as a primer for viral RNA replication and remains covalently bound to viral genomic RNA. VPg is uridylylated prior to priming replication into VPg-pUpU. The oriI viral genomic sequence may act as a template for this. The VPg-pUpU is then used as primer on the genomic RNA poly(A) by the RNA-dependent RNA polymerase to replicate the viral genome. During genome replication, the VPg-RNA linkage is removed by the host TDP2, thereby accelerating replication. During the late stage of the replication cycle, host TDP2 is excluded from sites of viral RNA synthesis and encapsidation, allowing for the generation of progeny virions.[ARBA:ARBA00054285] Capsid protein VP0: Component of immature procapsids, which is cleaved into capsid proteins VP4 and VP2 after maturation. Allows the capsid to remain inactive before the maturation step.[RuleBase:RU364118] Capsid protein VP1: Forms an icosahedral capsid of pseudo T=3 symmetry with capsid proteins VP2 and VP3. The capsid is 300 Angstroms in diameter, composed of 60 copies of each capsid protein and enclosing the viral positive strand RNA genome. Capsid protein VP1 mainly forms the vertices of the capsid. Capsid protein VP1 interacts with host cell receptor to provide virion attachment to target host cells. This attachment induces virion internalization. Tyrosine kinases are probably involved in the entry process. After binding to its receptor, the capsid undergoes conformational changes. Capsid protein VP1 N-terminus (that contains an amphipathic alpha-helix) and capsid protein VP4 are externalized. Together, they shape a pore in the host membrane through which viral genome is translocated to host cell cytoplasm. After genome has been released, the channel shrinks.[RuleBase:RU364118] Capsid protein VP2: Forms an icosahedral capsid of pseudo T=3 symmetry with capsid proteins VP2 and VP3. The capsid is 300 Angstroms in diameter, composed of 60 copies of each capsid protein and enclosing the viral positive strand RNA genome.[RuleBase:RU364118] Capsid protein VP3: Forms an icosahedral capsid of pseudo T=3 symmetry with capsid proteins VP2 and VP3. The capsid is 300 Angstroms in diameter, composed of 60 copies of each capsid protein and enclosing the viral positive strand RNA genome.[RuleBase:RU364118] Capsid protein VP4: Lies on the inner surface of the capsid shell. After binding to the host receptor, the capsid undergoes conformational changes. Capsid protein VP4 is released, Capsid protein VP1 N-terminus is externalized, and together, they shape a pore in the host membrane through which the viral genome is translocated into the host cell cytoplasm.[RuleBase:RU364118] Cysteine protease that cleaves viral polyprotein and specific host proteins. It is responsible for the autocatalytic cleavage between the P1 and P2 regions, which is the first cleavage occurring in the polyprotein. Also cleaves the host translation initiation factor EIF4G1, in order to shut down the capped cellular mRNA translation. Inhibits the host nucleus-cytoplasm protein and RNA trafficking by cleaving host members of the nuclear pores. Counteracts stress granule formation probably by antagonizing its assembly or promoting its dissassembly. Cleaves and inhibits host IFIH1/MDA5, thereby inhibiting the type-I IFN production and the establishment of the antiviral state. Cleaves and inhibits host MAVS, thereby inhibiting the type-I IFN production and the establishment of the antiviral state.[ARBA:ARBA00056557] Localizes the viral replication complex to the surface of membranous vesicles. It inhibits host cell endoplasmic reticulum-to-Golgi apparatus transport and causes the disassembly of the Golgi complex, possibly through GBF1 interaction. This would result in depletion of MHC, trail receptors and IFN receptors at the host cell surface. Plays an essential role in viral RNA replication by recruiting ACBD3 and PI4KB at the viral replication sites, thereby allowing the formation of the rearranged membranous structures where viral replication takes place.[ARBA:ARBA00045482] Protease 2A: Cysteine protease that cleaves viral polyprotein and specific host proteins.[RuleBase:RU364118] Protease 3C: Major viral protease that mediates proteolytic processing of the polyprotein. Cleaves host EIF5B, contributing to host translation shutoff. Cleaves also host PABPC1, contributing to host translation shutoff.[RuleBase:RU364118] Protein 2B: Plays an essential role in the virus replication cycle by acting as a viroporin. Creates a pore in the host reticulum endoplasmic and as a consequence releases Ca2+ in the cytoplasm of infected cell. In turn, high levels of cytoplasmic calcium may trigger membrane trafficking and transport of viral ER-associated proteins to viroplasms, sites of viral genome replication.[RuleBase:RU364118] Protein 2C: Induces and associates with structural rearrangements of intracellular membranes. Displays RNA-binding, nucleotide binding and NTPase activities. May play a role in virion morphogenesis and viral RNA encapsidation by interacting with the capsid protein VP3.[RuleBase:RU364118] Protein 3A: Localizes the viral replication complex to the surface of membranous vesicles. It inhibits host cell endoplasmic reticulum-to-Golgi apparatus transport and causes the disassembly of the Golgi complex, possibly through GBF1 interaction. This would result in depletion of MHC, trail receptors and IFN receptors at the host cell surface.[RuleBase:RU364118] Protein 3AB: Localizes the viral replication complex to the surface of membranous vesicles. Together with protein 3CD binds the Cis-Active RNA Element (CRE) which is involved in RNA synthesis initiation. Acts as a cofactor to stimulate the activity of 3D polymerase, maybe through a nucleid acid chaperone activity.[RuleBase:RU364118] Protein 3CD: Involved in the viral replication complex and viral polypeptide maturation. It exhibits protease activity with a specificity and catalytic efficiency that is different from protease 3C. Protein 3CD lacks polymerase activity. Protein 3CD binds to the 5'UTR of the viral genome.[RuleBase:RU364118] RNA-directed RNA polymerase: Replicates the viral genomic RNA on the surface of intracellular membranes. May form linear arrays of subunits that propagate along a strong head-to-tail interaction called interface-I. Covalently attaches UMP to a tyrosine of VPg, which is used to prime RNA synthesis. The positive stranded RNA genome is first replicated at virus induced membranous vesicles, creating a dsRNA genomic replication form. This dsRNA is then used as template to synthesize positive stranded RNA genomes. ss(+)RNA genomes are either translated, replicated or encapsidated.[RuleBase:RU364118] Viral protein genome-linked: acts as a primer for viral RNA replication and remains covalently bound to viral genomic RNA. VPg is uridylylated prior to priming replication into VPg-pUpU. The oriI viral genomic sequence may act as a template for this. The VPg-pUpU is then used as primer on the genomic RNA poly(A) by the RNA-dependent RNA polymerase to replicate the viral genome.[RuleBase:RU364118] Publication Abstract from PubMedZinc (Zn(2+)) plays essential roles in a plethora of physiological processes, including key functions as a neuromodulator. The zinc-activated channel (ZAC) belongs to the Cys-loop receptor (CLR) superfamily of pentameric ligand-gated ion channels, which also comprises receptors for the important neurotransmitters acetylcholine, serotonin, GABA and glycine. In contrast to these classical CLRs, which have been extensively explored over decades, ZAC remains poorly characterized despite its potential significance in mammals. Here, we present several cryo-EM structures of human ZAC, including the ligand-free resting state, the Zn(2+)-bound state, and several antagonist-bound states. In the Zn(2+)-bound structure, Zn(2+) ions bind to the subunit interfaces of the extracellular domain, corresponding to the canonical agonist-binding sites in the classical CLRs, and are primarily coordinated through cationâpi interactions with two aromatic residues. While the antagonist TTFB inhibits ZAC by insertion between the transmembrane M2 helices of adjacent subunits, d-tubocurarine acts in a dual manner by blocking the channel and interfering with agonist binding. Combined with mutagenesis and electrophysiological analysis, these evaluations highlight the distinctive structural and functional features of this atypical CLR. Structural basis of human zinc-activated channel (ZAC) signaling and modulation.,Zhou Z, Long Y, Chao Y, Yang C, Tang YQ, Shu Y, Zhu H, Jensen AA, Qu Q Cell Discov. 2026 Mar 31;12(1):23. doi: 10.1038/s41421-026-00878-5. PMID:41912481[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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