Highly selective inhibition of myosin motors provides the basis of potential therapeutic application.
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.
Structural Motility, Institut Curie, Paris Sciences et Lettres Research University, CNRS, UMR 144, F-75005 Paris, France.|Sorbonne Universités, Université Pierre et Marie Curie Univ Paris06, Sorbonne Universités, Institut de Formation Doctorale, 75252 Paris cedex 05, France.
Serena
S
Sirigu
Preclinical Research and Development, Cytokinetics, Inc., South San Francisco, CA 94080.
James J
JJ
Hartman
Structural Motility, Institut Curie, Paris Sciences et Lettres Research University, CNRS, UMR 144, F-75005 Paris, France.|Sorbonne Universités, Université Pierre et Marie Curie Univ Paris06, Sorbonne Universités, Institut de Formation Doctorale, 75252 Paris cedex 05, France.
Vicente José
0000-0002-1665-184X
VJ
Planelles-Herrero
Structural Motility, Institut Curie, Paris Sciences et Lettres Research University, CNRS, UMR 144, F-75005 Paris, France.|Sorbonne Universités, Université Pierre et Marie Curie Univ Paris06, Sorbonne Universités, Institut de Formation Doctorale, 75252 Paris cedex 05, France.
Virginie
V
Ropars
Preclinical Research and Development, Cytokinetics, Inc., South San Francisco, CA 94080.
Sheila
S
Clancy
Preclinical Research and Development, Cytokinetics, Inc., South San Francisco, CA 94080.
Xi
X
Wang
Preclinical Research and Development, Cytokinetics, Inc., South San Francisco, CA 94080.
Grace
G
Chuang
Preclinical Research and Development, Cytokinetics, Inc., South San Francisco, CA 94080.
Xiangping
X
Qian
Preclinical Research and Development, Cytokinetics, Inc., South San Francisco, CA 94080.
Pu-Ping
PP
Lu
Lovelace Respiratory Research Institute, Albuquerque, NM 87108-5127.
Edward
E
Barrett
Lovelace Respiratory Research Institute, Albuquerque, NM 87108-5127.
Karin
K
Rudolph
Lovelace Respiratory Research Institute, Albuquerque, NM 87108-5127.
Christopher
C
Royer
Preclinical Research and Development, Cytokinetics, Inc., South San Francisco, CA 94080.
Bradley P
BP
Morgan
Commissariat à l'Énergie Atomique, Direction des Sciences du Vivant, Institut de Biologie et Technologies de Saclay, Service d'Ingénierie Moléculaire des Protéines, 91191 Gif-sur-Yvette, France.
Enrico A
EA
Stura
Preclinical Research and Development, Cytokinetics, Inc., South San Francisco, CA 94080.
Fady I
FI
Malik
Structural Motility, Institut Curie, Paris Sciences et Lettres Research University, CNRS, UMR 144, F-75005 Paris, France; anne.houdusse@curie.fr.|Sorbonne Universités, Université Pierre et Marie Curie Univ Paris06, Sorbonne Universités, Institut de Formation Doctorale, 75252 Paris cedex 05, France.
Anne M
AM
Houdusse
D000199:Actins / Q000378:metabolism; D000495:Allosteric Site; D000818:Animals; D018360:Crystallography, X-Ray; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008958:Models, Molecular; D009126:Muscle Relaxation; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D054852:Small Molecule Libraries / Q000494:pharmacology*; D024745:Smooth Muscle Myosins / Q000037:antagonists & inhibitors* / Q000737:chemistry*
D000199:Actins; D054852:Small Molecule Libraries; D024745:Smooth Muscle Myosins
actin; drug design; molecular motor; myosin; specific allosteric drugs