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      Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor

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          Abstract

          <p id="P1">The kappa-opioid receptor (KOP) mediates the actions of opioids with hallucinogenic, dysphoric and analgesic activities. The design of KOP analgesics devoid of hallucinatory and dysphoric effects has been hindered by an incomplete structural and mechanistic understanding of KOP agonist actions. Here we provide a crystal structure of the human KOP in complex with the potent epoxymorphinan opioid agonist MP1104 and an active state stabilizing nanobody. Comparisons between inactive and active state opioid receptor structures reveal substantial conformational changes in the binding pocket, intracellular and extracellular regions. Extensive structural analysis and experimental validation illuminate key residues that propagate larger scale structural rearrangements and transducer binding that, collectively, elucidate the structural determinants of KOP pharmacology, function, and biased signaling. These molecular insights promise to accelerate the structure-guided design of safer and more effective kappa-opioid receptor therapeutics. </p><p id="P2">A crystal structure of the active κ-opioid receptor provides a guide for the development of safe and effective new analgesics </p>

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          Author and article information

          Journal
          Cell
          Cell
          Elsevier BV
          00928674
          January 2018
          January 2018
          : 172
          : 1-2
          : 55-67.e15
          Article
          10.1016/j.cell.2017.12.011
          5802374
          29307491
          2a786441-74b2-4dfc-9629-df835d2b3947
          © 2018

          http://www.elsevier.com/tdm/userlicense/1.0/

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