Highly selective inhibition of myosin motors provides the basis of potential therapeutic application
| Autor: | Pu-Ping Lu, Fady I. Malik, Bradley P. Morgan, Anne Houdusse, James J. Hartman, Edward G. Barrett, Karin Rudolph, Enrico A. Stura, Grace Chuang, Xiangping Qian, Virginie Ropars, Sheila Clancy, Christopher Royer, Serena Sirigu, Xi Wang, Vicente J. Planelles-Herrero |
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| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular 0301 basic medicine Muscle Relaxation Allosteric regulation Drug Evaluation Preclinical Biology Crystallography X-Ray Small Molecule Libraries Motor protein 03 medical and health sciences Dogs Myosin Molecular motor medicine Animals Humans Binding site Actin Multidisciplinary 030102 biochemistry & molecular biology Skeletal muscle Muscle Smooth Smooth Muscle Myosins Actins Rats 030104 developmental biology Muscle relaxation medicine.anatomical_structure PNAS Plus Biochemistry Biophysics Allosteric Site Protein Binding |
| Zdroj: | Proceedings of the National Academy of Sciences. 113 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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