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      Antibodies and venom peptides: new modalities for ion channels

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          Abstract

          <p class="first" id="P1">Ion channels play fundamental roles in both excitable and non-excitable tissues and therefore constitute attractive drug targets for a myriad of neurological, cardiovascular and metabolic diseases as well as for cancer and immunomodulation. However, achieving selectivity for specific ion channel subtypes with small molecule drugs has been challenging and there currently is a growing trend to target ion channels with biologics. One approach is to improve the pharmacokinetics of existing or novel venom derived peptides. In parallel, after initial studies with polyclonal antibodies demonstrated the technical feasibility of inhibiting channel function with antibodies, multiple preclinical programs are now using the full spectrum of available technologies to generate conventional monoclonal and engineered antibodies or nanobodies against extracellular loops of ion channels. After a summary of the current state of ion channel drug discovery, this review discusses recent developments using the purinergic receptor channel P2X7, the voltage-gated potassium channel <span style="font-variant: small-caps">K</span> <sub>V</sub>1.3 and the voltage-gated sodium channel Nav1.7 as examples of targeting ion channels with biologics. </p>

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          hERG potassium channels and cardiac arrhythmia.

          hERG potassium channels are essential for normal electrical activity in the heart. Inherited mutations in the HERG gene cause long QT syndrome, a disorder that predisposes individuals to life-threatening arrhythmias. Arrhythmia can also be induced by a blockage of hERG channels by a surprisingly diverse group of drugs. This side effect is a common reason for drug failure in preclinical safety trials. Insights gained from the crystal structures of other potassium channels have helped our understanding of the block of hERG channels and the mechanisms of gating.
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            Activation and allosteric modulation of a muscarinic acetylcholine receptor

            Despite recent advances in crystallography of G protein-coupled receptors (GPCRs), little is known about the mechanism of their activation process, as only the β2 adrenergic receptor (β2AR) and rhodopsin have been crystallized in fully active conformations. Here, we report the structure of an agonist-bound, active state of the human M2 muscarinic acetylcholine receptor stabilized by a G-protein mimetic camelid antibody fragment isolated by conformational selection using yeast surface display. In addition to the expected changes in the intracellular surface, the structure reveals larger conformational changes in the extracellular region and orthosteric binding site than observed in the active states of the β2AR and rhodopsin. We also report the structure of the M2 receptor simultaneously binding the orthosteric agonist iperoxo and the positive allosteric modulator LY2119620. This structure reveals that LY2119620 recognizes a largely pre-formed binding site in the extracellular vestibule of the iperoxo-bound receptor, inducing a slight contraction of this outer binding pocket. These structures offer important insights into activation mechanism and allosteric modulation of muscarinic receptors.
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              Cryo-EM Structure of the Open Human Ether-à-go-go -Related K + Channel hERG

              The human ether-à-go-go-related potassium channel (hERG, Kv11.1) is a voltage-dependent channel known for its role in repolarizing the cardiac action potential. hERG alteration by mutation or pharmacological inhibition produces Long QT syndrome and the lethal cardiac arrhythmia torsade de pointes. We have determined the molecular structure of hERG to 3.8 Å using cryo-electron microscopy. In this structure, the voltage sensors adopt a depolarized conformation, and the pore is open. The central cavity has an atypically small central volume surrounded by four deep hydrophobic pockets, which may explain hERG's unusual sensitivity to many drugs. A subtle structural feature of the hERG selectivity filter might correlate with its fast inactivation rate, which is key to hERG's role in cardiac action potential repolarization.
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                Author and article information

                Journal
                Nature Reviews Drug Discovery
                Nat Rev Drug Discov
                Springer Nature
                1474-1776
                1474-1784
                February 6 2019
                Article
                10.1038/s41573-019-0013-8
                6499689
                30728472
                3d18003f-7243-4e80-819d-2b30c071132f
                © 2019

                http://www.springer.com/tdm

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