6YSY

Skeletal Myosin bound to MPH-220, MgADP-VO4

Summary for 6YSY

• Entry DOI: 10.2210/pdb6ysy/pdb
• Descriptor: Myosin-4, Myosin light chain 1/3, skeletal muscle isoform, ADENOSINE-5'-DIPHOSPHATE, ... (7 entities in total)
• Functional Keywords: myofibril, muscle spasticity, actin binding, inhibitor, motor protein
• Biological source: Oryctolagus cuniculus (Rabbit); More
• Total number of polymer chains: 2
• Total formula weight: 245409.77

Authors

Canon, L.,Kikuti, C.M.,Gyimesi, M.,Malnasi-Csizmadia, A.,Houdusse, A. (deposition date: 2020-04-23, release date: 2021-03-03, Last modification date: 2024-01-24)

Primary citation

Gyimesi, M.,Horvath, A.I.,Turos, D.,Suthar, S.K.,Penzes, M.,Kurdi, C.,Canon, L.,Kikuti, C.,Ruppel, K.M.,Trivedi, D.V.,Spudich, J.A.,Lorincz, I.,Rauscher, A.A.,Kovacs, M.,Pal, E.,Komoly, S.,Houdusse, A.,Malnasi-Csizmadia, A.
Single Residue Variation in Skeletal Muscle Myosin Enables Direct and Selective Drug Targeting for Spasticity and Muscle Stiffness.
Cell, 183:335-346.e13, 2020

PubMed Abstract: Muscle spasticity after nervous system injuries and painful low back spasm affect more than 10% of global population. Current medications are of limited efficacy and cause neurological and cardiovascular side effects because they target upstream regulators of muscle contraction. Direct myosin inhibition could provide optimal muscle relaxation; however, targeting skeletal myosin is particularly challenging because of its similarity to the cardiac isoform. We identified a key residue difference between these myosin isoforms, located in the communication center of the functional regions, which allowed us to design a selective inhibitor, MPH-220. Mutagenic analysis and the atomic structure of MPH-220-bound skeletal muscle myosin confirmed the mechanism of specificity. Targeting skeletal muscle myosin by MPH-220 enabled muscle relaxation, in human and model systems, without cardiovascular side effects and improved spastic gait disorders after brain injury in a disease model. MPH-220 provides a potential nervous-system-independent option to treat spasticity and muscle stiffness.

PubMed: 33035452
DOI: 10.1016/j.cell.2020.08.050

Experimental method

X-RAY DIFFRACTION (3.246 Å)