1. Nanobodies as negative allosteric modulators for human calcium sensing receptor.
- Author
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Cui Q, Wang L, Wang H, Chen X, Han L, Geng T, Kou Y, Zhang W, Dai M, Qiao H, Sun Z, Li L, Lan Z, Xu H, Xu J, Dai Y, and Geng Y
- Subjects
- Humans, Receptors, Calcium-Sensing metabolism, Calcium metabolism, Single-Domain Antibodies, Hypocalcemia genetics, Hypercalcemia genetics
- Abstract
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
2+ i ) and suppress the G12/13 and ERK1/2 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)- Published
- 2024
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