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Nanobodies as negative allosteric modulators for human calcium sensing receptor.
Cui, Qianqian; Wang, Lu; Wang, Haonan; Chen, Xiaochen; Han, Li; Geng, Tengjie; Kou, Yongjun; Zhang, Wenqing; Dai, Mei; Qiao, Huarui; Sun, Zengchao; Li, Lingyun; Lan, Zhongyun; Xu, Hongxi; Xu, Jiaqiang; Dai, Yuanyuan; Geng, Yong.
Afiliação
  • Cui Q; 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.
  • Wang L; 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.
  • Wang H; 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.
  • Chen X; 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.
  • Han L; 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.
  • Geng T; 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.
  • Kou Y; 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.
  • Zhang W; 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.
  • Dai M; 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.
  • Qiao H; 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.
  • Sun Z; 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.
  • Li L; 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.
  • Lan Z; 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.
  • Xu H; School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: daiyuanyuan@cicams.ac.cn.
  • Xu J; NEST Lab, Department of Chemistry, College of Science, Shanghai University, Shanghai, 200444, China. Electronic address: xujiaqiang@shu.edu.cn.
  • Dai Y; Department of Pharmacy, National Cancer Center/ National Clinical Research Center for Cancer/Cancer Hospital, and Peking Union Medical College, Chinese Academy of Medical Science, Beijing, 100021, China. Electronic address: xuhongxi88@gmail.com.
  • Geng Y; 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; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: gengyong@simm.ac.cn.
Biochem Biophys Res Commun ; 695: 149401, 2024 Feb 05.
Article em En | MEDLINE | ID: mdl-38154264
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 (Ca2+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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Anticorpos de Domínio Único / Hipercalcemia / Hipocalcemia Limite: Humans Idioma: En Revista: Biochem Biophys Res Commun Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Anticorpos de Domínio Único / Hipercalcemia / Hipocalcemia Limite: Humans Idioma: En Revista: Biochem Biophys Res Commun Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China