{
  "abstract": "Cardiac myosin is the molecular motor that drives heart contraction, powered by the energy-source ATP and through its interaction with actin tracks. Direct modulators of cardiac myosin function are promising treatments for inherited heart disease and heart failure. The inherited heart disease hypertrophic cardiomyopathy affects 1 in 500 people and is the most common cause of sudden onset cardiac death in the young, causing approximately 12 deaths in the UK every week. Heart failure is an increasing worldwide public health issue with an estimated prevalence of 64 million people, a mortality rate of approximately 50% within five years of diagnosis, and an estimated cost to the economy of $346 billion. Current treatments improve heart function but not patient survival. Direct myosin modulators have the potential to do both. Yet, despite a range of pre-clinical studies, we still have very little idea as to how these modulators work at the molecular level, which hinders their clinical usage and development.Here we explore the effect of cardiac myosin modulators on myosin structure and dynamics by use of cryogenic electron microscopy and cross-linking mass spectrometry. We also explore the effectiveness of mavacamten as a myosin inhibitor in the presence of specific disease-causing mutations by in vitro motility assay.We show how the myosin modulators mavacamten, OM and aficamten affect myosin structure and dynamics and how their effectiveness maybe influenced by the presence of hypertrophic cardiomyopathy mutations.This work has the potential to identify patient populations that can benefit most from specific modulator treatment, to predict prospective adverse effects, and to inform on the design of improved myosin modulators with better long-term outcomes.",
  "authors": [
    {
      "affiliations": [
        "Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds (UoL), UK",
        "Astbury Centre for Structural Molecular Biology, UoL, UK",
        "School of Molecular and Cellular Biology, Faculty of Biological Sciences, UoL, UK"
      ],
      "name": "Sean N McMillan"
    },
    {
      "affiliations": [
        "Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds (UoL), UK",
        "Astbury Centre for Structural Molecular Biology, UoL, UK"
      ],
      "name": "Jaime Pitts"
    },
    {
      "affiliations": [
        "Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey 08854, USA"
      ],
      "name": "Donald A Winkelmann"
    },
    {
      "affiliations": [
        "Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds (UoL), UK",
        "Astbury Centre for Structural Molecular Biology, UoL, UK"
      ],
      "name": "Charlotte A Scarff"
    }
  ],
  "title": "BS40 Understanding how cardiac myosin modulators regulate function in health and disease",
  "uid": "53d7ff6e-b1b0-52e2-bb60-fb689691d70a"
}