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Highly selective inhibition of myosin motors provides the basis of potential therapeutic application.

Sirigu S, Hartman JJ, Planelles-Herrero VJ, Ropars V, Clancy S, Wang X, Chuang G, Qian X, Lu PP, Barrett E, Rudolph K, Royer C, Morgan BP, Stura EA, Malik FI, Houdusse AM
Proc Natl Acad Sci U S A 113 E7448-E7455 (2016)
Cited: 20 times
EuropePMC logo PMID: 27815532

Abstract

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.

Articles - 5m05 mentioned but not cited (3)

  1. Highly selective inhibition of myosin motors provides the basis of potential therapeutic application. Sirigu S, Hartman JJ, Planelles-Herrero VJ, Ropars V, Clancy S, Wang X, Chuang G, Qian X, Lu PP, Barrett E, Rudolph K, Royer C, Morgan BP, Stura EA, Malik FI, Houdusse AM. Proc Natl Acad Sci U S A 113 E7448-E7455 (2016)
  2. Molecular features of the UNC-45 chaperone critical for binding and folding muscle myosin. Hellerschmied D, Lehner A, Franicevic N, Arnese R, Johnson C, Vogel A, Meinhart A, Kurzbauer R, Deszcz L, Gazda L, Geeves M, Clausen T. Nat Commun 10 4781 (2019)
  3. Characterization of a novel MYO3A missense mutation associated with a dominant form of late onset hearing loss. Dantas VGL, Raval MH, Ballesteros A, Cui R, Gunther LK, Yamamoto GL, Alves LU, Bueno AS, Lezirovitz K, Pirana S, Mendes BCA, Yengo CM, Kachar B, Mingroni-Netto RC. Sci Rep 8 8706 (2018)


Reviews citing this publication (2)

  1. Three perspectives on the molecular basis of hypercontractility caused by hypertrophic cardiomyopathy mutations. Spudich JA. Pflugers Arch 471 701-717 (2019)
  2. Actin-Myosin Interaction: Structure, Function and Drug Discovery. Guhathakurta P, Prochniewicz E, Thomas DD. Int J Mol Sci 19 E2628 (2018)

Articles citing this publication (15)

  1. Mechanistic and structural basis for activation of cardiac myosin force production by omecamtiv mecarbil. Planelles-Herrero VJ, Hartman JJ, Robert-Paganin J, Malik FI, Houdusse A. Nat Commun 8 190 (2017)
  2. Plasmodium myosin A drives parasite invasion by an atypical force generating mechanism. Robert-Paganin J, Robblee JP, Auguin D, Blake TCA, Bookwalter CS, Krementsova EB, Moussaoui D, Previs MJ, Jousset G, Baum J, Trybus KM, Houdusse A. Nat Commun 10 3286 (2019)
  3. Drug specificity and affinity are encoded in the probability of cryptic pocket opening in myosin motor domains. Meller A, Lotthammer JM, Smith LG, Novak B, Lee LA, Kuhn CC, Greenberg L, Leinwand LA, Greenberg MJ, Bowman GR. Elife 12 e83602 (2023)
  4. Kinetic adaptation of human Myo19 for active mitochondrial transport to growing filopodia tips. Ušaj M, Henn A. Sci Rep 7 11596 (2017)
  5. Allosteric modulation of cardiac myosin dynamics by omecamtiv mecarbil. Hashem S, Tiberti M, Fornili A. PLoS Comput Biol 13 e1005826 (2017)
  6. Kinetic signatures of myosin-5B, the motor involved in microvillus inclusion disease. Heissler SM, Chinthalapudi K, Sellers JR. J Biol Chem 292 18372-18385 (2017)
  7. An intermediate along the recovery stroke of myosin VI revealed by X-ray crystallography and molecular dynamics. Blanc F, Isabet T, Benisty H, Sweeney HL, Cecchini M, Houdusse A. Proc Natl Acad Sci U S A 115 6213-6218 (2018)
  8. Phenamacril is a reversible and noncompetitive inhibitor of Fusarium class I myosin. Wollenberg RD, Taft MH, Giese S, Thiel C, Balázs Z, Giese H, Manstein DJ, Sondergaard TE. J Biol Chem 294 1328-1337 (2019)
  9. Synthesis and Evaluation of 4-Hydroxycoumarin Imines as Inhibitors of Class II Myosins. Brawley J, Etter E, Heredia D, Intasiri A, Nennecker K, Smith J, Welcome BM, Brizendine RK, Gould TW, Bell TW, Cremo C. J Med Chem 63 11131-11148 (2020)
  10. A Semi-High-Throughput Adaptation of the NADH-Coupled ATPase Assay for Screening Small Molecule Inhibitors. Radnai L, Stremel RF, Sellers JR, Rumbaugh G, Miller CA. J Vis Exp (2019)
  11. Designed mono- and di-covalent inhibitors trap modeled functional motions for Trypanosoma cruzi proline racemase in crystallography. Amaral PA, Autheman D, de Melo GD, Gouault N, Cupif JF, Goyard S, Dutra P, Coatnoan N, Cosson A, Monet D, Saul F, Haouz A, Uriac P, Blondel A, Minoprio P. PLoS Negl Trop Dis 12 e0006853 (2018)
  12. Comment Functional insights into the Magnaporthe oryzae class II myosin. Motaung TE, Tsilo TJ. Virulence 8 1091-1095 (2017)
  13. MyosinA is a druggable target in the widespread protozoan parasite Toxoplasma gondii. Kelsen A, Kent RS, Snyder AK, Wehri E, Bishop SJ, Stadler RV, Powell C, Martorelli di Genova B, Rompikuntal PK, Boulanger MJ, Warshaw DM, Westwood NJ, Schaletzky J, Ward GE. PLoS Biol 21 e3002110 (2023)
  14. Recovering Actives in Multi-Antitarget and Target Design of Analogs of the Myosin II Inhibitor Blebbistatin. Roman BI, Guedes RC, Stevens CV, García-Sosa AT. Front Chem 6 179 (2018)
  15. Mechanism of small molecule inhibition of Plasmodium falciparum myosin A informs antimalarial drug design. Moussaoui D, Robblee JP, Robert-Paganin J, Auguin D, Fisher F, Fagnant PM, Macfarlane JE, Schaletzky J, Wehri E, Mueller-Dieckmann C, Baum J, Trybus KM, Houdusse A. Nat Commun 14 3463 (2023)


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