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@ARTICLE{Kaiser:912181,
      author       = {Kaiser, Jesko and Gertzen, Christoph G. W. and Bernauer,
                      Tamara and Höfner, Georg and Niessen, Karin V. and Seeger,
                      Thomas and Paintner, Franz F. and Wanner, Klaus T. and
                      Worek, Franz and Thiermann, Horst and Gohlke, Holger},
      title        = {{A} novel binding site in the nicotinic acetylcholine
                      receptor for {MB}327 can explain its allosteric modulation
                      relevant for organophosphorus-poisoning treatment},
      journal      = {Toxicology letters},
      volume       = {373},
      issn         = {0378-4274},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier Science},
      reportid     = {FZJ-2022-05397},
      pages        = {160-171},
      year         = {2023},
      abstract     = {Organophosphorus compounds (OPCs) are highly toxic
                      compounds that can block acetylcholine esterase (AChE) and
                      thereby indirectly lead to an overstimulation of muscarinic
                      and nicotinic acetylcholine receptors (nAChRs). The current
                      treatment with atropine and AChE reactivators (oximes) is
                      insufficient to prevent toxic effects, such as respiratory
                      paralysis, after poisonings with various OPCs. Thus,
                      alternative treatment options are required to increase
                      treatment efficacy. Novel therapeutics, such as the
                      bispyridinium non-oxime MB327, have been found to
                      reestablish neuromuscular transmission by interacting
                      directly with nAChR, probably via allosteric mechanisms. To
                      rationally design new, more potent drugs addressing nAChR,
                      knowledge of the binding mode of MB327 is fundamental.
                      However, the binding pocket of MB327 has remained elusive.
                      Here, we identify a new potential allosteric binding pocket
                      (MB327-PAM-1) of MB327 located at the transition of the
                      extracellular to the transmembrane region using blind
                      docking experiments and molecular dynamics simulations.
                      MB327 forms striking interactions with the receptor at this
                      site. The interacting amino acids are highly conserved among
                      different subunits and different species. Correspondingly,
                      MB327 can interact with several nAChR subtypes from
                      different species. We predict by rigidity analysis that
                      MB327 exerts an allosteric effect on the orthosteric binding
                      pocket and the transmembrane domain after binding to
                      MB327-PAM-1. Furthermore, free ligand diffusion MD
                      simulations reveal that MB327 also has an affinity to the
                      orthosteric binding pocket, which agrees with recently
                      published results that related bispyridinium compounds show
                      inhibitory effects via the orthosteric binding site. The
                      newly identified binding site allowed us to predict
                      structural modifications of MB327, resulting in the more
                      potent resensitizers PTM0062 and PTM0063.},
      cin          = {NIC / JSC / IBI-7 / IBG-4},
      ddc          = {610},
      cid          = {I:(DE-Juel1)NIC-20090406 / I:(DE-Juel1)JSC-20090406 /
                      I:(DE-Juel1)IBI-7-20200312 / I:(DE-Juel1)IBG-4-20200403},
      pnm          = {5111 - Domain-Specific Simulation $\&$ Data Life Cycle Labs
                      (SDLs) and Research Groups (POF4-511) / Forschergruppe
                      Gohlke $(hkf7_20200501)$ / 5241 - Molecular Information
                      Processing in Cellular Systems (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5111 / $G:(DE-Juel1)hkf7_20200501$ /
                      G:(DE-HGF)POF4-5241},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {36503818},
      UT           = {WOS:000928240000002},
      doi          = {10.1016/j.toxlet.2022.11.018},
      url          = {https://juser.fz-juelich.de/record/912181},
}