纳米抗体作为人钙敏感受体的负变构调节剂。
Nanobodies as negative allosteric modulators for human calcium sensing receptor.
机构信息
NEST Lab, Department of Chemistry, College of Science, Shanghai University, Shanghai, 200444, China; The CAS Key Laboratory of Receptor Research, Stake Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
The CAS Key Laboratory of Receptor Research, Stake Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
出版信息
Biochem Biophys Res Commun. 2024 Feb 5;695:149401. doi: 10.1016/j.bbrc.2023.149401. Epub 2023 Dec 21.
Human calcium sensing receptor (CaSR) senses calcium ion concentrations in vivo and is an important class of drug targets. Mutations in the receptor can lead to disorders of calcium homeostasis, including hypercalcemia and hypocalcemia. Here, 127 CaSR-targeted nanobodies were generated from camels, and four nanobodies with inhibitory function were further identified. Among these nanobodies, NB32 can effectively inhibit the mobilization of intracellular calcium ions (Ca) and suppress the G and ERK signaling pathways downstream of CaSR. Moreover, it enhanced the inhibitory effect of the calcilytics as a negative allosteric modulator (NAM). We determined the structure of complex and found NB32 bound to LB2 (Ligand-binding 2) domain of CaSR to prevent the interaction of LB2 domains of two protomers to stabilize the inactive state of CaSR.
人钙敏感受体（CaSR）在体内感知钙离子浓度，是一类重要的药物靶点。受体的突变可导致钙稳态紊乱，包括高钙血症和低钙血症。在此，我们从骆驼中产生了 127 种靶向 CaSR 的纳米抗体，并进一步鉴定出了四种具有抑制功能的纳米抗体。在这些纳米抗体中，NB32 可以有效抑制细胞内钙离子（Ca）的动员，并抑制 CaSR 下游的 G 和 ERK 信号通路。此外，它作为负变构调节剂（NAM）增强了钙敏感受体激动剂的抑制作用。我们确定了复合物的结构，发现 NB32 与 CaSR 的 LB2（配体结合 2）结构域结合，以阻止两个前体的 LB2 结构域相互作用，从而稳定 CaSR 的无活性状态。
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