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Insulin: The Receptor and Signaling Pathways01:28

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Insulin action is mediated through a receptor tyrosine kinase, akin to the IGF-1 receptor. The number of receptors per cell varies significantly, from 40 on erythrocytes to 300,000 on adipocytes and hepatocytes. The insulin receptor consists of linked α/β subunit dimers, forming a heterotetramer glycoprotein with two extracellular α subunits and two β subunits spanning the membrane. The α subunits inhibit the inherent tyrosine kinase activity of the β subunits, but...
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The pancreatic islets comprising only 1%-2% of the volume are highly vascularized and innervated mini-organs. They contain five endocrine cell types, including β cells that secrete insulin, which is synthesized as a single polypeptide chain, preproinsulin, processed to proinsulin, and finally to insulin and C-peptide. This process is complex and regulated, involving the Golgi complex, the endoplasmic reticulum, and the secretory granules of the β cell.
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Amyloid fibrils are aggregates of misfolded proteins.  Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils. 
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The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
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The endoplasmic reticulum (ER) of pancreatic β-cells synthesizes preproinsulin, which consists of a signal peptide, A and B chains, and a C-peptide. Preproinsulin is then cleaved and folded into proinsulin, which translocates to the Golgi apparatus for sorting and packaging into secretory granules. In these granules, enzymatic clipping generates insulin and C-peptide.
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Glucagon-like Receptor Agonists01:24

Glucagon-like Receptor Agonists

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Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...
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アミリン受容体フェノタイプの構造的基礎

Jianjun Cao1,2, Matthew J Belousoff1,2, Yi-Lynn Liang1

  • 1Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Victoria, Australia.

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|March 24, 2022
PubMed
まとめ

アミリン受容体 (AMYR) とカルシトニン受容体 (CTR) はペプチドを異なる形で結合する. これらの特定の結合メカニズムを理解することは,AMYRを標的とした新しい肥満治療の開発に不可欠です.

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科学分野:

  • 生物化学
  • 構造生物学
  • 薬理学について

背景:

  • アミリン受容体 (AMYR) は,カルシトニン受容体 (CTR) と受容体活性調節タンパク質 (RAMP) のヘテロダイマーである.
  • AMYRとCTRは肥満治療の標的ですが,それらのペプチド結合と選択性の分子基盤は不明です.
  • これらの相互作用を理解することは 合理的な薬剤設計に不可欠です

研究 の 目的:

  • アミリンとCTベースのペプチドに結合した活性AMYRの構造と動態を決定する.
  • AMYRとCTRにおけるペプチド結合と選択性の基礎となる分子メカニズムを解明する.
  • AMYRを標的とした新しい治療法の開発を促す.

主な方法:

  • アミリンで複合された活性AMYRの冷凍電子顕微鏡構造を決定した.
  • AMY1RとAMY2Rの構造は,サーモンCT (sCT) とヒトCT (hCT) で決定された.
  • アミリン,sCT,hCTで複合したCTRの構造を決定した.

主要な成果:

  • アミリン結合のAMYR複合体は,RAMP制約バイパスモチーフを特徴とする保存された形状を採用した.
  • CT結合のAMYR複合体は,アミリン結合複合体とは異なる構造を示した.
  • CT-bound AMYR構造は,CT-bound CTR構造と重なり合っており,共通の結合要素を示しています.

結論:

  • CTベースのペプチドによるAMYRの活性化は,アミリンによる活性化とは機械的に異なる.
  • 特定された構造的差異は,AMYRとCTRの選択性についての洞察を提供します.
  • これらの発見は,肥満および他の代謝障害に対するAMYRアゴニストの治療開発に重要な意味を持つ.