Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Biochemistry
2020 Feb 25;597:836-850. doi: 10.1021/acs.biochem.9b01098.
Show Gene links
Show Anatomy links
Structural Determinants Mediating Tertiapin Block of Neuronal Kir3.2 Channels.
Patel D
,
Kuyucak S
,
Doupnik CA
.
???displayArticle.abstract???
Tertiapin (TPN) is a 21 amino acid venom peptide from Apis mellifera that inhibits certain members of the inward rectifier potassium (Kir) channel family at a nanomolar affinity with limited specificity. Structure-based computational simulations predict that TPN behaves as a pore blocker; however, the molecular determinants mediating block of neuronal Kir3 channels have been inconclusive and unvalidated. Here, using molecular docking and molecular dynamics (MD) simulations with 'potential of mean force' (PMF) calculations, we investigated the energetically most favored interaction of TPN with several Kir3.x channel structures. The resulting binding model for Kir3.2-TPN complexes was then tested by targeted mutagenesis of the predicted contact sites, and their impact on the functional channel block was measured electrophysiologically. Together, our findings indicate that a high-affinity TPN block of Kir3.2 channels involves a pore-inserting lysine side chain requiring (1) hydrophobic interactions at a phenylalanine ring surrounding the channel pore and (2) electrostatic interactions with two adjacent Kir3.2 turret regions. Together, these interactions collectively stabilize high-affinity toxin binding to the Kir3.2 outer vestibule, which orients the ε-amino group of TPN-K21 to occupy the outermost K+ binding site of the selectivity filter. The structural determinants for the TPN block described here also revealed a favored subunit arrangement for assembled Kir3.x heteromeric channels, in addition to a multimodal binding capacity of TPN variants consistent with the functional dyad model for polybasic peptide pore blockers. These novel findings will aid efforts in re-engineering the TPN pharmacophore to develop peptide variants having unique and distinct Kir channel blocking properties.
Aiyar,
Topology of the pore-region of a K+ channel revealed by the NMR-derived structures of scorpion toxins.
1995, Pubmed
Aiyar,
Topology of the pore-region of a K+ channel revealed by the NMR-derived structures of scorpion toxins.
1995,
Pubmed
Alessandri-Haber,
Mapping the functional anatomy of BgK on Kv1.1, Kv1.2, and Kv1.3. Clues to design analogs with enhanced selectivity.
1999,
Pubmed
,
Xenbase
Banerjee,
Structure of a pore-blocking toxin in complex with a eukaryotic voltage-dependent K(+) channel.
2013,
Pubmed
Blednov,
GIRK2 deficient mice. Evidence for hyperactivity and reduced anxiety.
,
Pubmed
Blichowski,
The GIRK2 subunit is involved in IS-like seizures induced by GABA(B) receptor agonists.
2015,
Pubmed
Chen,
Accurate determination of the binding free energy for KcsA-charybdotoxin complex from the potential of mean force calculations with restraints.
2011,
Pubmed
Chen,
Developing a comparative docking protocol for the prediction of peptide selectivity profiles: investigation of potassium channel toxins.
2012,
Pubmed
Chen,
Constitutively active G-protein-gated inwardly rectifying K+ channels in dendrites of hippocampal CA1 pyramidal neurons.
2005,
Pubmed
Dauplais,
On the convergent evolution of animal toxins. Conservation of a diad of functional residues in potassium channel-blocking toxins with unrelated structures.
1997,
Pubmed
Dominguez,
HADDOCK: a protein-protein docking approach based on biochemical or biophysical information.
2003,
Pubmed
Doupnik,
Identification of Aethina tumida Kir Channels as Putative Targets of the Bee Venom Peptide Tertiapin Using Structure-Based Virtual Screening Methods.
2019,
Pubmed
,
Xenbase
Doupnik,
Measuring the modulatory effects of RGS proteins on GIRK channels.
2004,
Pubmed
,
Xenbase
Doupnik,
Venom-derived peptides inhibiting Kir channels: Past, present, and future.
2017,
Pubmed
Doupnik,
A computational design approach for virtual screening of peptide interactions across K(+) channel families.
2015,
Pubmed
Drici,
The bee venom peptide tertiapin underlines the role of I(KACh) in acetylcholine-induced atrioventricular blocks.
2000,
Pubmed
,
Xenbase
Duprat,
Heterologous multimeric assembly is essential for K+ channel activity of neuronal and cardiac G-protein-activated inward rectifiers.
1995,
Pubmed
,
Xenbase
Dutertre,
Use of venom peptides to probe ion channel structure and function.
2010,
Pubmed
Felix,
Characterization of Kir1.1 channels with the use of a radiolabeled derivative of tertiapin.
2006,
Pubmed
Gauldie,
The peptide components of bee venom.
1976,
Pubmed
Han,
Structural basis of a potent peptide inhibitor designed for Kv1.3 channel, a therapeutic target of autoimmune disease.
2008,
Pubmed
Hibino,
Inwardly rectifying potassium channels: their structure, function, and physiological roles.
2010,
Pubmed
Hilder,
Conductance properties of the inwardly rectifying channel, Kir3.2: molecular and Brownian dynamics study.
2013,
Pubmed
Humphrey,
VMD: visual molecular dynamics.
1996,
Pubmed
Jelacic,
Functional expression and characterization of G-protein-gated inwardly rectifying K+ channels containing GIRK3.
1999,
Pubmed
,
Xenbase
Jelacic,
Functional and biochemical evidence for G-protein-gated inwardly rectifying K+ (GIRK) channels composed of GIRK2 and GIRK3.
2000,
Pubmed
Jin,
Synthesis of a stable form of tertiapin: a high-affinity inhibitor for inward-rectifier K+ channels.
1999,
Pubmed
,
Xenbase
Jin,
Mechanisms of inward-rectifier K+ channel inhibition by tertiapin-Q.
1999,
Pubmed
,
Xenbase
Jin,
A novel high-affinity inhibitor for inward-rectifier K+ channels.
1998,
Pubmed
,
Xenbase
Jouirou,
Toxin determinants required for interaction with voltage-gated K+ channels.
2004,
Pubmed
Kalia,
From foe to friend: using animal toxins to investigate ion channel function.
2015,
Pubmed
Kanjhan,
Tertiapin-Q blocks recombinant and native large conductance K+ channels in a use-dependent manner.
2005,
Pubmed
,
Xenbase
Kitamura,
Tertiapin potently and selectively blocks muscarinic K(+) channels in rabbit cardiac myocytes.
2000,
Pubmed
Kofuji,
Evidence that neuronal G-protein-gated inwardly rectifying K+ channels are activated by G beta gamma subunits and function as heteromultimers.
1995,
Pubmed
,
Xenbase
Lesage,
Molecular properties of neuronal G-protein-activated inwardly rectifying K+ channels.
1995,
Pubmed
,
Xenbase
Li,
Molecular dynamics of the honey bee toxin tertiapin binding to Kir3.2.
2016,
Pubmed
Llamosas,
Deletion of GIRK2 Subunit of GIRK Channels Alters the 5-HT1A Receptor-Mediated Signaling and Results in a Depression-Resistant Behavior.
2015,
Pubmed
Lüscher,
Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease.
2010,
Pubmed
Lüscher,
G protein-coupled inwardly rectifying K+ channels (GIRKs) mediate postsynaptic but not presynaptic transmitter actions in hippocampal neurons.
1997,
Pubmed
MacKinnon,
Mechanism of charybdotoxin block of the high-conductance, Ca2+-activated K+ channel.
1988,
Pubmed
Mahdavi,
Molecular dynamics study of binding of µ-conotoxin GIIIA to the voltage-gated sodium channel Na(v)1.4.
2014,
Pubmed
Mahdavi,
Systematic study of binding of μ-conotoxins to the sodium channel NaV1.4.
2014,
Pubmed
Marker,
Spinal G-protein-gated K+ channels formed by GIRK1 and GIRK2 subunits modulate thermal nociception and contribute to morphine analgesia.
2004,
Pubmed
Mitrovic,
Contribution of GIRK2-mediated postsynaptic signaling to opiate and alpha 2-adrenergic analgesia and analgesic sex differences.
2003,
Pubmed
Montalbano,
Pharmacological Characterization of 5-HT1A Autoreceptor-Coupled GIRK Channels in Rat Dorsal Raphe 5-HT Neurons.
2015,
Pubmed
Montandon,
G-protein-gated Inwardly Rectifying Potassium Channels Modulate Respiratory Depression by Opioids.
2016,
Pubmed
Mouhat,
Contribution of the functional dyad of animal toxins acting on voltage-gated Kv1-type channels.
2005,
Pubmed
Patel,
Computational Study of Binding of μ-Conotoxin GIIIA to Bacterial Sodium Channels NaVAb and NaVRh.
2016,
Pubmed
Pessia,
Subunit positional effects revealed by novel heteromeric inwardly rectifying K+ channels.
1996,
Pubmed
,
Xenbase
Phillips,
Scalable molecular dynamics with NAMD.
2005,
Pubmed
Ramu,
Short variable sequence acquired in evolution enables selective inhibition of various inward-rectifier K+ channels.
2004,
Pubmed
,
Xenbase
Rashid,
Free energy simulations of binding of HsTx1 toxin to Kv1 potassium channels: the basis of Kv1.3/Kv1.1 selectivity.
2014,
Pubmed
Rashid,
Affinity and selectivity of ShK toxin for the Kv1 potassium channels from free energy simulations.
2012,
Pubmed
Rashid,
A potent and Kv1.3-selective analogue of the scorpion toxin HsTX1 as a potential therapeutic for autoimmune diseases.
2014,
Pubmed
Robinson,
Venom peptides as therapeutics: advances, challenges and the future of venom-peptide discovery.
2017,
Pubmed
Rubinstein,
Divergent regulation of GIRK1 and GIRK2 subunits of the neuronal G protein gated K+ channel by GalphaiGDP and Gbetagamma.
2009,
Pubmed
,
Xenbase
Safavi-Hemami,
Pain therapeutics from cone snail venoms: From Ziconotide to novel non-opioid pathways.
2019,
Pubmed
Shen,
Treating autoimmune disorders with venom-derived peptides.
2017,
Pubmed
Signorini,
Normal cerebellar development but susceptibility to seizures in mice lacking G protein-coupled, inwardly rectifying K+ channel GIRK2.
1997,
Pubmed
Silverman,
Subunit stoichiometry of a heteromultimeric G protein-coupled inward-rectifier K+ channel.
1996,
Pubmed
,
Xenbase
Vanommeslaeghe,
CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields.
2010,
Pubmed
Velimirovic,
The K+ channel inward rectifier subunits form a channel similar to neuronal G protein-gated K+ channel.
1996,
Pubmed
,
Xenbase
Verdier,
Identification of a novel pharmacophore for peptide toxins interacting with K+ channels.
2005,
Pubmed
,
Xenbase
Walsh,
Targeting GIRK Channels for the Development of New Therapeutic Agents.
2011,
Pubmed
Webb,
Comparative Protein Structure Modeling Using MODELLER.
2014,
Pubmed
Whorton,
Crystal structure of the mammalian GIRK2 K+ channel and gating regulation by G proteins, PIP2, and sodium.
2011,
Pubmed
,
Xenbase
Xu,
Solution structure of tertiapin determined using nuclear magnetic resonance and distance geometry.
1993,
Pubmed
Zhang,
Gating properties of GIRK channels activated by Galpha(o)- and Galpha(i)-coupled muscarinic m2 receptors in Xenopus oocytes: the role of receptor precoupling in RGS modulation.
2002,
Pubmed
,
Xenbase
Zhang,
Why do we study animal toxins?
2015,
Pubmed
de Vries,
HADDOCK versus HADDOCK: new features and performance of HADDOCK2.0 on the CAPRI targets.
2007,
Pubmed
