Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Cryo-EM Facility at MIT.nano, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Nat Chem Biol. 2024 Dec;20(12):1577-1585. doi: 10.1038/s41589-024-01620-6. Epub 2024 May 14.
G-protein-coupled receptors (GPCRs) are key regulators of human physiology and are the targets of many small-molecule research compounds and therapeutic drugs. While most of these ligands bind to their target GPCR with high affinity, selectivity is often limited at the receptor, tissue and cellular levels. Antibodies have the potential to address these limitations but their properties as GPCR ligands remain poorly characterized. Here, using protein engineering, pharmacological assays and structural studies, we develop maternally selective heavy-chain-only antibody ('nanobody') antagonists against the angiotensin II type I receptor and uncover the unusual molecular basis of their receptor antagonism. We further show that our nanobodies can simultaneously bind to angiotensin II type I receptor with specific small-molecule antagonists and demonstrate that ligand selectivity can be readily tuned. Our work illustrates that antibody fragments can exhibit rich and evolvable pharmacology, attesting to their potential as next-generation GPCR modulators.
G 蛋白偶联受体（GPCRs）是人体生理学的关键调节因子，也是许多小分子研究化合物和治疗药物的靶点。虽然这些配体中的大多数与它们的靶标 GPCR 具有高亲和力结合，但在受体、组织和细胞水平上，选择性通常受到限制。抗体具有解决这些限制的潜力，但它们作为 GPCR 配体的特性仍未得到充分表征。在这里，我们使用蛋白质工程、药理学测定和结构研究，开发了针对血管紧张素 II 型 1 受体的母体选择性重链单域抗体（“纳米抗体”）拮抗剂，并揭示了它们受体拮抗作用的不寻常分子基础。我们进一步表明，我们的纳米抗体可以与血管紧张素 II 型 1 受体与特定的小分子拮抗剂同时结合，并证明配体选择性可以轻松调节。我们的工作表明，抗体片段可以表现出丰富和可进化的药理学，证明它们有潜力成为下一代 GPCR 调节剂。
