Academic Journal
Structural basis for human Cav3.2 inhibition by selective antagonists
| العنوان: | Structural basis for human Cav3.2 inhibition by selective antagonists |
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| المؤلفون: | Huang, Jian, Fan, Xiao, Jin, Xueqin, Lyu, Chen, Guo, Qinmeng, Liu, Tao, Chen, Jiaofeng, Davakan, Amaël, Lory, Philippe, Yan, Nieng |
| المساهمون: | Princeton University, Rockefeller University New York, Tsinghua University Beijing (THU), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), ANR-11-LABX-0015,ICST,Canaux ioniques d'intérêt thérapeutique(2011) |
| المصدر: | ISSN: 1001-0602. |
| بيانات النشر: | HAL CCSD Nature Publishing Group |
| سنة النشر: | 2024 |
| المجموعة: | Université de Montpellier: HAL |
| مصطلحات موضوعية: | [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], [SCCO.NEUR]Cognitive science/Neuroscience |
| الوصف: | International audience ; The Cav3.2 subtype of T-type calcium channels has been targeted for developing analgesics and anti-epileptics for its role in pain and epilepsy. Here we present the cryo-EM structures of Cav3.2 alone and in complex with four T-type calcium channel selective antagonists with overall resolutions ranging from 2.8 Å to 3.2 Å. The four compounds display two binding poses. ACT-709478 and TTA-A2 both place their cyclopropylphenyl-containing ends in the central cavity to directly obstruct ion flow, meanwhile extending their polar tails into the IV-I fenestration. TTA-P2 and ML218 project their 3,5-dichlorobenzamide groups into the II-III fenestration and place their hydrophobic tails in the cavity to impede ion permeation. The fenestration-penetrating mode immediately affords an explanation for the state-dependent activities of these antagonists. Structure-guided mutational analysis identifies several key residues that determine the T-type preference of these drugs. The structures also suggest the role of an endogenous lipid in stabilizing drug binding in the central cavity. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/38605177; PUBMED: 38605177; PUBMEDCENTRAL: PMC11143251 |
| DOI: | 10.1038/s41422-024-00959-8 |
| الاتاحة: | https://hal.science/hal-04549967 https://hal.science/hal-04549967v1/document https://hal.science/hal-04549967v1/file/Huang%20et%20al_Cav3.2%20structure%20%26%20pharmaco_Cell%20Res%202024.pdf https://doi.org/10.1038/s41422-024-00959-8 |
| Rights: | info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.E525D2C |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41422-024-00959-8 |
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