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Structural insight into allosteric modulation of protease-activated receptor 2

机译：蛋白酶激活受体2的变构调节的结构见解。

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摘要

Protease-activated receptors ( PARs) are a family of G-proteincoupled receptors ( GPCRs) that are irreversibly activated by proteolytic cleavage of the N terminus, which unmasks a tethered peptide ligand that binds and activates the transmembrane receptor domain, eliciting a cellular cascade in response to inflammatory signals and other stimuli. PARs are implicated in a wide range of diseases, such as cancer and inflammation(1-3). PARs have been the subject of major pharmaceutical research efforts(3) but the discovery of small-molecule antagonists that effectively bind them has proved challenging. The only marketed drug targeting a PAR is vorapaxar(4), a selective antagonist of PAR1 used to prevent thrombosis. The structure of PAR1 in complex with vorapaxar has been reported previously(5). Despite sequence homology across the PAR isoforms, discovery of PAR2 antagonists has been less successful, although GB88 has been described as a weak antagonist6. Here we report crystal structures of PAR2 in complex with two distinct antagonists and a blocking antibody. The antagonist AZ8838 binds in a fully occluded pocket near the extracellular surface. Functional and binding studies reveal that AZ8838 exhibits slow binding kinetics, which is an attractive feature for a PAR2 antagonist competing against a tethered ligand. Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling. We also show that a blocking antibody antigen-binding fragment binds to the extracellular surface of PAR2, preventing access of the tethered ligand to the peptide-binding site. These structures provide a basis for the development of selective PAR2 antagonists for a range of therapeutic uses.
机译：蛋白酶激活受体（PARs）是一类G蛋白偶联受体（GPCR），其通过N端的蛋白水解切割而不可逆地激活，这揭示了结合并激活跨膜受体结构域的束缚肽配体，从而引发了细胞级联反应对炎症信号和其他刺激的反应。 PAR与多种疾病有关，例如癌症和炎症（1-3）。 PAR一直是主要药物研究的主题（3），但是发现有效结合它们的小分子拮抗剂已被证明具有挑战性。靶向PAR的唯一市售药物是vorapaxar（4），一种可预防血栓形成的PAR1选择性拮抗剂。以前已经报道了与vorapaxar复合的PAR1的结构（5）。尽管在PAR同工型上具有序列同源性，但是尽管GB88被描述为弱拮抗剂，但PAR2拮抗剂的发现却不太成功。在这里，我们报告PAR2的晶体结构与两种不同的拮抗剂和一种阻断抗体复合。拮抗剂AZ8838结合在细胞外表面附近完全堵塞的口袋中。功能和结合研究表明，AZ8838表现出缓慢的结合动力学，这是PAR2拮抗剂与束缚配体竞争的诱人特征。拮抗剂AZ3451与螺旋束外的一个远端变构位点结合。我们建议拮抗剂结合防止受体激活和信号转导所需的结构重排。我们还显示，阻断性抗体抗原结合片段与PAR2的细胞外表面结合，阻止了拴系配体进入肽结合位点。这些结构为开发用于多种治疗用途的选择性PAR2拮抗剂提供了基础。

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  • 来源
    《Nature》 |2017年第7652期|112-115|共4页
  • 作者

    Cheng Robert K. Y.; Fiez-Vandal Cedric; Schlenker Oliver; Edman Karl; Aggeler Birte; Brown Dean G.; Brown Giles A.; Cooke Robert M.; Dumelin Christoph E.; Dore Andrew S.; Geschwindner Stefan; Grebner Christoph; Hermansson Nils-Olov; Jazayeri Ali; Johansson Patrik; Leong Louis; Prihandoko Rudi; Rappas Mathieu; Soutter Holly; Snijder Arjan; Sundstrom Linda; Tehan Benjamin; Thornton Peter; Troast Dawn; Wiggin Giselle; Zhukov Andrei; Marshall Fiona H.; Dekker Niek;

  • 作者单位

    Heptares Therapeut Ltd, BioPk,Broadwater Rd, Welwyn Garden City AL7 3AX, Herts, England;

    Heptares Therapeut Ltd, BioPk,Broadwater Rd, Welwyn Garden City AL7 3AX, Herts, England;

    Heptares Therapeut Ltd, BioPk,Broadwater Rd, Welwyn Garden City AL7 3AX, Herts, England;

    Astra Zeneca, Discovery Sci Innovat Med & Early Dev Biotech Uni, Pepparedsleden 1, S-43183 Molndal, Sweden;

    Biotechne, 614 McKinley Pl NE, Minneapolis, MN 55413 USA;

    AstraZeneca R&D, Discovery Sci Innovat Med & Early Dev Biotech Uni, 35 Gatehouse Dr, Waltham, MA 02451 USA;

    Heptares Therapeut Ltd, BioPk,Broadwater Rd, Welwyn Garden City AL7 3AX, Herts, England;

    Heptares Therapeut Ltd, BioPk,Broadwater Rd, Welwyn Garden City AL7 3AX, Herts, England;

    X Chem Inc, 100 Beaver St, Waltham, MA 02453 USA;

    Heptares Therapeut Ltd, BioPk,Broadwater Rd, Welwyn Garden City AL7 3AX, Herts, England;

    Astra Zeneca, Discovery Sci Innovat Med & Early Dev Biotech Uni, Pepparedsleden 1, S-43183 Molndal, Sweden;

    Astra Zeneca, Cardiovasc & Metab Dis Innovat Med & Early Dev Bi, Pepparedsleden 1, S-43183 Molndal, Sweden;

    Astra Zeneca, Discovery Sci Innovat Med & Early Dev Biotech Uni, Pepparedsleden 1, S-43183 Molndal, Sweden;

    Heptares Therapeut Ltd, BioPk,Broadwater Rd, Welwyn Garden City AL7 3AX, Herts, England;

    Heptares Therapeut Ltd, BioPk,Broadwater Rd, Welwyn Garden City AL7 3AX, Herts, England|Astra Zeneca, Discovery Sci Innovat Med & Early Dev Biotech Uni, Pepparedsleden 1, S-43183 Molndal, Sweden;

    Biotechne, 614 McKinley Pl NE, Minneapolis, MN 55413 USA;

    Heptares Therapeut Ltd, BioPk,Broadwater Rd, Welwyn Garden City AL7 3AX, Herts, England;

    Heptares Therapeut Ltd, BioPk,Broadwater Rd, Welwyn Garden City AL7 3AX, Herts, England;

    X Chem Inc, 100 Beaver St, Waltham, MA 02453 USA;

    Astra Zeneca, Discovery Sci Innovat Med & Early Dev Biotech Uni, Pepparedsleden 1, S-43183 Molndal, Sweden;

    Astra Zeneca, Discovery Sci Innovat Med & Early Dev Biotech Uni, Pepparedsleden 1, S-43183 Molndal, Sweden;

    Heptares Therapeut Ltd, BioPk,Broadwater Rd, Welwyn Garden City AL7 3AX, Herts, England;

    Astra Zeneca, Neurosc Innovat Med & Early Dev Biotech Unit, Granta Pk, Cambridge CB21 6GH, England;

    X Chem Inc, 100 Beaver St, Waltham, MA 02453 USA;

    Heptares Therapeut Ltd, BioPk,Broadwater Rd, Welwyn Garden City AL7 3AX, Herts, England;

    Heptares Therapeut Ltd, BioPk,Broadwater Rd, Welwyn Garden City AL7 3AX, Herts, England;

    Heptares Therapeut Ltd, BioPk,Broadwater Rd, Welwyn Garden City AL7 3AX, Herts, England;

    Astra Zeneca, Discovery Sci Innovat Med & Early Dev Biotech Uni, Pepparedsleden 1, S-43183 Molndal, Sweden;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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