5N6A

Cardiac muscle myosin motor domain in the pre-powerstroke state

Summary for 5N6A

• Entry DOI: 10.2210/pdb5n6a/pdb
• Descriptor: Myosin-7, ADENOSINE-5'-DIPHOSPHATE, PHOSPHATE ION, ... (6 entities in total)
• Functional Keywords: myosin, cardiac, pre-powerstroke, motor protein
• Biological source: Bos taurus (cattle)
• Cellular location: Cytoplasm, myofibril : Q9BE39
• Total number of polymer chains: 1
• Total formula weight: 95431.23

Authors

Planelles-Herrero, V.J.,Hartman, J.J.,Robert-Paganin, J.,Malik, F.I.,Houdusse, A. (deposition date: 2017-02-14, release date: 2017-08-09, Last modification date: 2024-01-17)

Primary citation

Planelles-Herrero, V.J.,Hartman, J.J.,Robert-Paganin, J.,Malik, F.I.,Houdusse, A.
Mechanistic and structural basis for activation of cardiac myosin force production by omecamtiv mecarbil.
Nat Commun, 8:190-190, 2017

PubMed Abstract: Omecamtiv mecarbil is a selective, small-molecule activator of cardiac myosin that is being developed as a potential treatment for heart failure with reduced ejection fraction. Here we determine the crystal structure of cardiac myosin in the pre-powerstroke state, the most relevant state suggested by kinetic studies, both with (2.45 Å) and without (3.10 Å) omecamtiv mecarbil bound. Omecamtiv mecarbil does not change the motor mechanism nor does it influence myosin structure. Instead, omecamtiv mecarbil binds to an allosteric site that stabilizes the lever arm in a primed position resulting in accumulation of cardiac myosin in the primed state prior to onset of cardiac contraction, thus increasing the number of heads that can bind to the actin filament and undergo a powerstroke once the cardiac cycle starts. The mechanism of action of omecamtiv mecarbil also provides insights into uncovering how force is generated by molecular motors.Omecamtiv mecarbil (OM) is a cardiac myosin activator that is currently in clinical trials for heart failure treatment. Here, the authors give insights into its mode of action and present the crystal structure of OM bound to bovine cardiac myosin, which shows that OM stabilizes the pre-powerstroke state of myosin.

PubMed: 28775348
DOI: 10.1038/s41467-017-00176-5

Experimental method

X-RAY DIFFRACTION (3.1 Å)