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Adhesion GPCRs (ADGRs) contain a GPCR autoproteolysis-inducing (GAIN) domain that is proximal to the receptor N-terminus and undergoes autoproteolysis at a highly conserved GPCR proteolysis (GPS) site to generate the N-terminal fragment (NTF) and transmembrane C-terminal fragment (CTF). Dissociation of NTF reveals a peptide tethered agonist (TA) which is responsible for the activation of the ADGRs. The NTF-bound ADGRs contain the encrypted TA that assumes a β-strand configuration within the GAIN domain, which is markedly different from a U-shaped α-helical configuration of TA in the active cryo-EM structures of ADGRs.

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Docosahexaenoic acid-containing phospholipid (PL-DHA) exhibits superior bioavailability compared to conventional DHA formulations. Derived primarily from Antarctic krill or enzymatic synthesis, PL-DHA's molecular architecture-specifically its position-dependent distribution within the glycerol backbone and polar headgroup variations-critically influences membrane dynamics. Sn-1 position DHA generates "U-shaped" configurations affecting membrane fluidity, while sn-2 position maintains "hairpin" conformations optimal for enzymatic recognition.

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An Allosteric Model for Electromechanical Coupling in Cardiac CNBD Channels.

bioRxiv

August 2025

Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, 1100 South Grand Blvd., St. Louis, MO, USA 63104.

Ion channels in the cyclic nucleotide-binding domain (CNBD) family, including hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and human ether-à-go-go-related gene (hERG) channels, play pivotal roles in regulating cardiac action potentials. HCN channels are uniquely activated by hyperpolarization, rather than depolarization, a critical mechanism for controlling the involuntary pacemaker activity of the heart. In contrast, hERG channels are depolarization-activated and mediate K currents essential for action potential repolarization.

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Unraveling the therapeutic landscape of approved non-peptide macrocycles.

Acta Pharm Sin B

July 2025

Tianjian Laboratory of Advanced Biomedical Sciences, Institute of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou 450000, China.

Non-peptide macrocyclic drugs possess unique structural advantages that allow them to target various biomolecules of interest and thus show therapeutic potential against various diseases such as cancer, infectious diseases, etc. This review article examines 34 non-peptide macrocyclic drugs approved between 2000 and 2024, with a particular focus on the optimization process of representative macrocyclic drugs such as natural macrocycles, natural product-inspired macrocycles, and -designed macrocycles. We discuss their structural characteristics, highlighting how conformational rigidity and enhanced target specificity contribute to their efficacy.

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Monoclonal antibody G2, obtained via immunization with the chicken prion protein (ChPrP), has unique antigen-binding specificity. G2 specifically binds to the ChPrP-derived peptide (Pep18mer) as expected, but also to three other peptides. In this study, we determined the crystal structures of G2 single-chain Fv antibodies covalently linked to Pep18mer and another peptide, PepH4P6.

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