scholarly journals Structural basis for drug-induced allosteric changes to human β-cardiac myosin motor activity

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Donald A. Winkelmann ◽  
Eva Forgacs ◽  
Matthew T. Miller ◽  
Ann M. Stock
Keyword(s):  
Motor Activity ◽  
Structural Basis ◽  
Cardiac Myosin ◽  
Drug Induced ◽  
Myosin Motor

scholarly journals Myosin and gelsolin cooperate in actin filament severing and actomyosin motor activity

2020 ◽  
pp. jbc.RA120.015863
Author(s):  
Venukumar Vemula ◽  
Tamás Huber ◽  
Marko Ušaj ◽  
Beáta Bugyi ◽  
Alf Mansson
Keyword(s):  
Motor Activity ◽  
Actin Filament ◽  
Single Molecule ◽  
Actin Filaments ◽  
Actin Binding ◽  
In Vitro Motility Assay ◽  
Cooperative Effects ◽  
Myosin Motor ◽  
Filament Dynamics

Actin is a major intracellular protein with key functions in cellular motility, signaling and structural rearrangements. Its dynamic behavior, such as polymerisation and depolymerisation of actin filaments in response to intra- and extracellular cues, is regulated by an abundance of actin binding proteins. Out of these, gelsolin is one of the most potent for filament severing. However, myosin motor activity also fragments actin filaments through motor induced forces, suggesting that these two proteins could cooperate to regulate filament dynamics and motility. To test this idea, we used an in vitro motility assay, where actin filaments are propelled by surface-adsorbed heavy meromyosin (HMM) motor fragments. This allows studies of both motility and filament dynamics using isolated proteins. Gelsolin, at both nanomolar and micromolar Ca2+ concentration, appreciably enhanced actin filament severing caused by HMM-induced forces at 1 mM MgATP, an effect that was increased at higher HMM motor density. This finding is consistent with cooperativity between actin filament severing by myosin-induced forces and by gelsolin. We also observed reduced sliding velocity of the HMM-propelled filaments in the presence of gelsolin, providing further support of myosin-gelsolin cooperativity. Total internal reflection fluorescence microscopy based single molecule studies corroborated that the velocity reduction was a direct effect of gelsolin-binding to the filament and revealed different filament severing pattern of stationary and HMM propelled filaments. Overall, the results corroborate cooperative effects between gelsolin-induced alterations in the actin filaments and changes due to myosin motor activity leading to enhanced F-actin severing of possible physiological relevance.

scholarly journals Actin Network Architecture Can Determine Myosin Motor Activity

Science ◽  
2012 ◽  
Vol 336 (6086) ◽  
pp. 1310-1314 ◽  
Author(s):  
A.-C. Reymann ◽  
R. Boujemaa-Paterski ◽  
J.-L. Martiel ◽  
C. Guerin ◽  
W. Cao ◽  
...  
Keyword(s):  
Motor Activity ◽  
Network Architecture ◽  
Actin Network ◽  
Myosin Motor

scholarly journals Filopod Extension Requires MyTH4-Ferm Myosin Motor Activity

2015 ◽  
Vol 108 (2) ◽  
pp. 303a
Author(s):  
Karl J. Petersen ◽  
G.W. Gant Luxton ◽  
Margaret A. Titus
Keyword(s):  
Motor Activity ◽  
Myosin Motor

P057 WIRELESS ELECTRODE PATCHES SHOW INTRAPATIENT REPRODUCIBILITY IN A LONGITUDINAL STUDY OF PATIENTS WITH CROHN’S DISEASE IN REMISSION

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S16-S16
Author(s):  
Steve Axelrod ◽  
Lindsay Axelrod ◽  
Anand Navalgund ◽  
Estelle Spear ◽  
Akshar Patel ◽  
...  
Keyword(s):  
Small Intestine ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Motor Activity ◽  
Myoelectric Activity ◽  
Drug Induced ◽  
Ipod Touch ◽  
Frequency Spectra ◽  
Non Invasive ◽  
Specific Frequency

Abstract Background Crohn’s disease (CD) patients would benefit from a non-invasive indicator of gut function to better predict changes in disease state, such as the onset of flare. A study of CD patients using non-invasive wireless electrode patches (G-Tech Medical, Mountain View, CA) that read myoelectric signals from the gut over 3 days is underway at Stanford University’s IBD center. The study will include 40 patients presenting in flare and 30 in remission to be tested at t=0, 1, 3 and 6 months. In addition, one-time tests will be performed on 20 healthy controls. Aims Herein, we report on the first 6 CD patients tested at t=0 and 1 month while in remission. Methods Each patient wore 3 abdominal patches (each 2.7” diameter) for 3 consecutive days while pursuing regular daily activities and meals (Figure 1). Each patch recorded 4 channels of myoelectric activity from the stomach, small intestine and colon, and transmitted the raw data to an iPod Touch, which relayed the data to a secure cloud server. Data were later downloaded and processed to remove artifacts, create frequency spectra, and search them for peaks representing rhythmic motor activity. We find that, nominally, stomach activity appears at 3 cycles/minute (cpm), small intestine at 6–12 cpm, and colon at 12–25 cpm. Results Figure 2 shows peak spectra for the 6 patients at t=0 and 1 month. Individual peaks represent motor activity at a specific frequency associated with the stomach, small intestine, or colon. Each patient has a unique overall pattern, or GutPrint, reflecting the frequencies and levels of activity of their GI motility. The GutPrint for each individual reproduces well at the second test and is easily recognizable for each subject. Although the peak amplitudes may vary, virtually all of the peaks that appear at specific frequencies at t=0 are also present at 1 month representing a quantifiable signature that reflects each patient’s unique motility. Conclusion The G-Tech patch system provides a practical and noninvasive, physiologic means of measuring motor activity of the gut over multiple days. Its intra-patient reproducibility allows for the possibility of measuring changes to gut performance over time, whether naturally- or drug-induced, showing promise in CD monitoring.

scholarly journals Mechanism and Specificity of Pentachloropseudilin-mediated Inhibition of Myosin Motor Activity

2011 ◽  
Vol 286 (34) ◽  
pp. 29700-29708 ◽  
Author(s):  
Krishna Chinthalapudi ◽  
Manuel H. Taft ◽  
René Martin ◽  
Sarah M. Heissler ◽  
Matthias Preller ◽  
...  
Keyword(s):  
Motor Activity ◽  
Myosin Motor

scholarly journals Perspectives of a myosin motor activator agent with increased selectivity

2018 ◽  
Vol 96 (7) ◽  
pp. 676-680
Author(s):  
Péter Nánási ◽  
István Komáromi ◽  
János Almássy
Keyword(s):  
In Silico ◽  
Clinical Performance ◽  
Ryanodine Receptors ◽  
In Silico Analysis ◽  
Docking Studies ◽  
Cardiac Myosin ◽  
In Silico Docking ◽  
Myosin Motor ◽  
Omecamtiv Mecarbil ◽  
Silico Analysis

Clinical treatment of heart failure is still not fully solved. A novel class of agents, the myosin motor activators, acts directly on cardiac myosin resulting in an increased force generation and prolongation of contraction. Omecamtiv mecarbil, the lead molecule of this group, is now in human phase 3 displaying promising clinical performance. However, omecamtiv mecarbil is not selective to myosin, because it readily binds to and activates cardiac ryanodine receptors (RyR-2), an effect that may cause complications in case of overdose. In this study, in silico analysis was performed to investigate the docking of omecamtiv mecarbil and other structural analogues to cardiac myosin heavy chain and RyR-2 to select the structure that has a higher selectivity to myosin over RyR-2. In silico docking studies revealed that omecamtiv mecarbil has comparable affinity to myosin and RyR-2: the respective Kd values are 0.60 and 0.87 μmol/L. Another compound, CK-1032100, has much lower affinity to RyR-2 than omecamtiv mecarbil, while it still has a moderate affinity to myosin. It was concluded that further research starting from the chemical structure of CK-1032100 may result a better myosin activator burdened probably less by the RyR-2 binding side effect. It also is possible, however, that the selectivity of omecamtiv mecarbil to myosin over RyR-2 cannot be substantially improved, because similar moieties seem to be responsible for the high affinity to both myosin and RyR-2.

Confinement Of Myosin Motor Activity On Trimethylchlorosilane Surface By Ultra Violet Light Exposure For Nano-Technology Applications

2008 ◽  
Vol 40 (Supplement) ◽  
pp. S297
Author(s):  
Madhukar B. Kolli ◽  
Hideyo Takatsuki ◽  
Devashish Desai ◽  
Kevin M. Rice ◽  
Sunil Kakarla ◽  
...  
Keyword(s):  
Motor Activity ◽  
Light Exposure ◽  
Ultra Violet ◽  
Nano Technology ◽  
Ultra Violet Light ◽  
Myosin Motor ◽  
Violet Light ◽  
Technology Applications

scholarly journals Harmonic Force Spectroscopy Reveals a Force-Velocity Curve from a Single Human Beta Cardiac Myosin Motor

2014 ◽  
Vol 106 (2) ◽  
pp. 453a
Author(s):  
Jongmin Sung ◽  
Suman Nag ◽  
Christian Vestergaard ◽  
Kim Mortensen ◽  
Henrik Flyvbjerg ◽  
...  
Keyword(s):  
Force Spectroscopy ◽  
Velocity Curve ◽  
Cardiac Myosin ◽  
Harmonic Force ◽  
Myosin Motor ◽  
Force Velocity

scholarly journals Structural basis of drug-induced aggregation of HIV-integrase

2017 ◽  
Vol 73 (a1) ◽  
pp. a410-a410
Author(s):  
Kushol Gupta ◽  
Grant Eilers ◽  
Vesa Turkki ◽  
Young Hwang ◽  
Gregory D. Van Duyne ◽  
...  
Keyword(s):  
Structural Basis ◽  
Hiv Integrase ◽  
Drug Induced ◽  
Induced Aggregation

scholarly journals A PIP2 substitute mediates voltage sensor-pore coupling in KCNQ activation

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Yongfeng Liu ◽  
Xianjin Xu ◽  
Junyuan Gao ◽  
Moawiah M. Naffaa ◽  
Hongwu Liang ◽  
...  
Keyword(s):  
Ventricular Myocytes ◽  
Membrane Lipids ◽  
Voltage Sensor ◽  
Structural Basis ◽  
Drug Induced ◽  
Kcnq Channels ◽  
Voltage Dependent ◽  
Pore Opening ◽  
Action Potential Prolongation ◽  
Voltage Sensor Domain

AbstractKCNQ family K+ channels (KCNQ1-5) in the heart, nerve, epithelium and ear require phosphatidylinositol 4,5-bisphosphate (PIP2) for voltage dependent activation. While membrane lipids are known to regulate voltage sensor domain (VSD) activation and pore opening in voltage dependent gating, PIP2 was found to interact with KCNQ1 and mediate VSD-pore coupling. Here, we show that a compound CP1, identified in silico based on the structures of both KCNQ1 and PIP2, can substitute for PIP2 to mediate VSD-pore coupling. Both PIP2 and CP1 interact with residues amongst a cluster of amino acids critical for VSD-pore coupling. CP1 alters KCNQ channel function due to different interactions with KCNQ compared with PIP2. We also found that CP1 returned drug-induced action potential prolongation in ventricular myocytes to normal durations. These results reveal the structural basis of PIP2 regulation of KCNQ channels and indicate a potential approach for the development of anti-arrhythmic therapy.

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