Inhibitory and stimulatory micropeptides preferentially bind to different conformations of the cardiac calcium pump

Discovery of Novel 2,3-Dihydro-1H-indene-5-sulfonamide NLRP3 Inflammasome Inhibitors Targeting Colon as a Potential Therapy for Colitis

“…Compounds that contain five or more rotatable bonds typically possess multiple molecular conformations, making it challenging to bind to their targets in the desired conformation . As a result, the affinity of these lead compounds to the targets of interest is reduced, and the unrestricted conformations may bind to other biomolecules, leading to poor selectivity and unexpected toxicity. , To address these issues, the cyclization strategy has emerged as the most straightforward approach to achieve conformational restriction, and it has been extensively used in drug design . Here in this research, we employed cyclization and a scaffold hopping strategy to cyclize the phenylethylamine fragment in the structure of JC124 and YQ128, resulting in 2,3-dihydro-1 H -indene-based sulfonamide derivatives (Figure ).…”

The Meeting of Micropeptides with Major Ca2+ Pumps in Inner Membranes—Consideration of a New Player, SERCA1b

“…According to a model, DWORF modifies the membrane bilayer and stabilizes SERCA conformations that predominate at elevated calcium [ 68 ]. It has been hypothesized that the function of these peptides may be related to their reciprocal preference for different intermediate conformations of SERCA [ 70 ]. Indeed, PLN binds best to the E1-ATP state of SERCA which occurs at low calcium ( Figure 3 ).…”

“…However, this process is rate-limited by the dissociation of PLN monomers from pentamers. The computer model in [ 70 ] suggested a functional impact of these interactions so that they exaggerate the response of SERCA to the change of calcium levels. When the heart is relaxed (diastole) the calcium level and SERCA activity are low and the pump activity is further inhibited by the increased binding of PLN.…”

“…The further inhibition at low Ca 2+ and the stimulation at high Ca 2+ can enhance the efficiency of energy use because the ATP consumption is conserved until the calcium transport is most effective and needed. Another interesting observation is, that PLN can be trapped in pentamers because of the increasing phosphorylation by PKA and CaMKII in response to adrenergic stimulation at a faster heart rate and at high Ca 2+ [ 70 ]. This might even contribute to the positive force–frequency relationship when faster heart rate results in more forceful contraction.…”

“…This might even contribute to the positive force–frequency relationship when faster heart rate results in more forceful contraction. This mechanism has been put forward as an insightful explanation for PLN–SERCA–DWORF interaction [ 70 ]. Recently it has been shown that a kink induced by Pro(15) of DWORF is primarily responsible for stimulation of SERCA [ 71 ].…”