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Article Dans Une Revue Proceedings of the National Academy of Sciences of the United States of America Année : 2016

Highly selective inhibition of myosin motors provides the basis of potential therapeutic application

James Hartman
  • Fonction : Auteur
Vicente José Planelles-Herrero
Sheila Clancy
  • Fonction : Auteur
Xi Wang
  • Fonction : Auteur
Grace Chuang
  • Fonction : Auteur
Xiangping Qian
  • Fonction : Auteur
Pu-Ping Lu
  • Fonction : Auteur
Edward Barrett
  • Fonction : Auteur
Karin Rudolph
  • Fonction : Auteur
Christopher Royer
  • Fonction : Auteur
Bradley Morgan
  • Fonction : Auteur
Enrico Stura
  • Fonction : Auteur
Fady Malik
  • Fonction : Auteur

Résumé

Direct inhibition of smooth muscle myosin (SMM) is a potential means to treat hypercontractile smooth muscle diseases. The selective inhibitor CK-2018571 prevents strong binding to actin and promotes muscle relaxation in vitro and in vivo. The crystal structure of the SMM/drug complex reveals that CK-2018571 binds to a novel allosteric pocket that opens up during the “recovery stroke” transition necessary to reprime the motor. Trapped in an intermediate of this fast transition, SMM is inhibited with high selectivity compared with skeletal muscle myosin (IC50 = 9 nM and 11,300 nM, respectively), although all of the binding site residues are identical in these motors. This structure provides a starting point from which to design highly specific myosin modulators to treat several human diseases. It further illustrates the potential of targeting transition intermediates of molecular machines to develop exquisitely selective pharmacological agents.
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Dates et versions

hal-04041234 , version 1 (23-03-2023)

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Serena Sirigu, James Hartman, Vicente José Planelles-Herrero, Virginie Ropars, Sheila Clancy, et al.. Highly selective inhibition of myosin motors provides the basis of potential therapeutic application. Proceedings of the National Academy of Sciences of the United States of America, 2016, 113 (47), ⟨10.1073/pnas.1609342113⟩. ⟨hal-04041234⟩
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