The structural arrangement of amino acid residues in native enzymes underlies their remarkable catalytic properties,t hus providing an otable point of reference for designing potent yet simple biomimetic catalysts.H erein, we describe am inimalistic approach to construct ad ipeptide-based nanosuperstructure with enzyme-like activity.T he self-assembled biocatalyst comprises one peptide as as ingle building block, readily synthesized from histidine.Through coordination with zinc ion, the peptide self-assembly procedure allows the formation of supramolecular b-sheet ordered nanocrystals, which can be used as basic units to further construct higherorder superstructure.A sar esult, remarkable hydrolysis activity and enduring stability are demonstrated. Our work exemplifies the use of ab ioinspired supramolecular assembly approach to develop next-generation biocatalysts for biotechnological applications.
The Ca 2+ -activated SK4 K + channel is gated by Ca 2+ –calmodulin (CaM) and is expressed in immune cells, brain, and heart. A cryoelectron microscopy (cryo-EM) structure of the human SK4 K + channel recently revealed four CaM molecules per channel tetramer, where the apo CaM C-lobe and the holo CaM N -lobe interact with the proximal carboxyl terminus and the linker S4–S5, respectively, to gate the channel. Here, we show that phosphatidylinositol 4-5 bisphosphate (PIP2) potently activates SK4 channels by docking to the boundary of the CaM-binding domain. An allosteric blocker, BA6b9, was designed to act to the CaM–PIP2-binding domain, a previously untargeted region of SK4 channels, at the interface of the proximal carboxyl terminus and the linker S4–S5. Site-directed mutagenesis, molecular docking, and patch-clamp electrophysiology indicate that BA6b9 inhibits SK4 channels by interacting with two specific residues, Arg191 and His192 in the linker S4–S5, not conserved in SK1–SK3 subunits, thereby conferring selectivity and preventing the Ca 2+ –CaM N -lobe from properly interacting with the channel linker region. Immunohistochemistry of the SK4 channel protein in rat hearts showed a widespread expression in the sarcolemma of atrial myocytes, with a sarcomeric striated Z-band pattern, and a weaker occurrence in the ventricle but a marked incidence at the intercalated discs. BA6b9 significantly prolonged atrial and atrioventricular effective refractory periods in rat isolated hearts and reduced atrial fibrillation induction ex vivo. Our work suggests that inhibition of SK4 K + channels by targeting drugs to the CaM–PIP2-binding domain provides a promising anti-arrhythmic therapy.
The application of stereochemically defined acyclic fully substituted enolates of ketones to the enantioselective synthesis of quaternary carbon stereocenters would be highly valuable. Herein, we describe an approach leading to the formation of several new stereogenic centers through a combined metalation-addition of a carbonyl-carbamoyl transfer to reveal in situ stereodefined α,α-disubstituted enolates of ketone as a single stereoisomer. This approach could produce a series of aldol and Mannich products from enol carbamate with excellent diastereomeric ratios.
The structural arrangement of amino acid residues in native enzymes underlies their remarkable catalytic properties,t hus providing an otable point of reference for designing potent yet simple biomimetic catalysts.H erein, we describe am inimalistic approach to construct ad ipeptide-based nanosuperstructure with enzyme-like activity.T he self-assembled biocatalyst comprises one peptide as as ingle building block, readily synthesized from histidine.Through coordination with zinc ion, the peptide self-assembly procedure allows the formation of supramolecular b-sheet ordered nanocrystals, which can be used as basic units to further construct higherorder superstructure.A sar esult, remarkable hydrolysis activity and enduring stability are demonstrated. Our work exemplifies the use of ab ioinspired supramolecular assembly approach to develop next-generation biocatalysts for biotechnological applications.
The formation of amyloid-like structures by metabolites is associated with several inborn errors of metabolism (IEMs). These structures display most of the biological, chemical and physical properties of protein amyloids. However, the molecular interactions underlying the assembly remain elusive, and so far, no modulating therapeutic agents are available for clinical use. Chemical chaperones are known to inhibit protein and peptide amyloid formation and stabilize misfolded enzymes. Here, we provide an in-depth characterization of the inhibitory effect of osmolytes and hydrophobic chemical chaperones on metabolite assemblies, thus extending their functional repertoire. We applied a combined in vivo-in vitro-in silico approach and show their ability to inhibit metabolite amyloid-induced toxicity and reduce cellular amyloid content in yeast. We further used various biophysical techniques demonstrating direct inhibition of adenine self-assembly and alteration of fibril morphology by chemical chaperones. Using a scaffold-based approach, we analyzed the physiochemical properties of various dimethyl sulfoxide derivatives and their role in inhibiting metabolite self-assembly. Lastly, we employed whole-atom molecular dynamics simulations to elucidate the role of hydrogen bonds in osmolyte inhibition. Our results imply a dual mode of action of chemical chaperones as IEMs therapeutics, that could be implemented in the rational design of novel lead-like molecules.
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