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首页> 外文期刊>Marine Drugs >Kunitz-Type Peptide HCRG21 from the Sea Anemone Heteractis crispa Is a Full Antagonist of the TRPV1 Receptor
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Kunitz-Type Peptide HCRG21 from the Sea Anemone Heteractis crispa Is a Full Antagonist of the TRPV1 Receptor

机译:海葵Heteractis crispa的Kunitz型肽HCRG21是TRPV1受体的完全拮抗剂。

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摘要

Sea anemone venoms comprise multifarious peptides modulating biological targets such as ion channels or receptors. The sequence of a new Kunitz-type peptide, HCRG21, belonging to the Heteractis crispa RG (HCRG) peptide subfamily was deduced on the basis of the gene sequence obtained from the Heteractis crispa cDNA. HCRG21 shares high structural homology with Kunitz-type peptides APHC1–APHC3 from H. crispa , and clusters with the peptides from so named “analgesic cluster” of the HCGS peptide subfamily but forms a separate branch on the NJ-phylogenetic tree. Three unique point substitutions at the N-terminus of the molecule, Arg1, Gly2, and Ser5, distinguish HCRG21 from other peptides of this cluster. The trypsin inhibitory activity of recombinant HCRG21 (rHCRG21) was comparable with the activity of peptides from the same cluster. Inhibition constants for trypsin and α-chymotrypsin were 1.0 × 10 ?7 and 7.0 × 10 ?7 M, respectively. Electrophysiological experiments revealed that rHCRG21 inhibits 95% of the capsaicin-induced current through transient receptor potential family member vanilloid 1 (TRPV1) and has a half-maximal inhibitory concentration of 6.9 ± 0.4 μM. Moreover, rHCRG21 is the first full peptide TRPV1 inhibitor, although displaying lower affinity for its receptor in comparison with other known ligands. Macromolecular docking and full atom Molecular Dynamics (MD) simulations of the rHCRG21–TRPV1 complex allow hypothesizing the existence of two feasible, intra- and extracellular, molecular mechanisms of blocking. These data provide valuable insights in the structural and functional relationships and pharmacological potential of bifunctional Kunitz-type peptides.
机译:海葵毒液包含多种肽,可调节生物靶标,例如离子通道或受体。基于从脆皮杂种菊cDNA获得的基因序列推导属于脆皮杂种RG(HCRG)肽亚家族的新的库尼兹型肽HCRG21的序列。 HCRG21与H.crispa的Kunitz型肽APHC1-APHC3具有高度的结构同源性,并与HCGS肽亚家族的所谓“镇痛簇”的肽簇聚,但在NJ系统发育树上形成了一个独立的分支。分子N端的三个独特的点取代,Arg1,Gly2和Ser5,将HCRG21与该簇的其他肽区分开。重组HCRG21(rHCRG21)的胰蛋白酶抑制活性与来自同一簇的肽的活性相当。胰蛋白酶和α-胰凝乳蛋白酶的抑制常数分别为1.0×10×7 M和7.0×10×7M。电生理实验表明,rHCRG21通过瞬时受体电位家族成员香草酸1(TRPV1)抑制了95%的辣椒素诱导电流,其半数抑制浓度为6.9±0.4μM。此外,rHCRG21是第一个全肽TRPV1抑制剂,尽管与其他已知配体相比,对它的受体显示出较低的亲和力。 rHCRG21–TRPV1复合物的大分子对接和全原子分子动力学(MD)模拟可以假设存在两种可行的封闭分子内和细胞外分子机制。这些数据为双功能Kunitz型肽的结构和功能关系以及药理潜力提供了有价值的见解。

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