EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Structural basis for human Ca3.2 inhibition by selective antagonists.
ジャーナル・号・ページ	Cell Res, Year 2024
掲載日	2024年4月11日
著者	Jian Huang / Xiao Fan / Xueqin Jin / Chen Lyu / Qinmeng Guo / Tao Liu / Jiaofeng Chen / Amaël Davakan / Philippe Lory / Nieng Yan /
PubMed 要旨	The Ca3.2 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 Ca3.2 alone ...The Ca3.2 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 Ca3.2 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.
リンク	Cell Res / PubMed:38605177
手法	EM (単粒子)
解像度	2.8 - 3.2 Å
構造データ	43991 9ayg EMDB-43991, PDB-9ayg: Cryo-EM structure of apo state human Cav3.2 手法: EM (単粒子) / 解像度: 3.0 Å 43992 9ayh EMDB-43992, PDB-9ayh: Cryo-EM structure of human Cav3.2 with TTA-A2 手法: EM (単粒子) / 解像度: 3.1 Å 43993 9ayj EMDB-43993, PDB-9ayj: Cryo-EM structure of human Cav3.2 with TTA-P2 手法: EM (単粒子) / 解像度: 3.2 Å 43994 9ayk EMDB-43994, PDB-9ayk: Cryo-EM structure of human Cav3.2 with ML218 手法: EM (単粒子) / 解像度: 3.0 Å 43995 9ayl EMDB-43995, PDB-9ayl: Cryo-EM structure of human Cav3.2 with ACT-709478 手法: EM (単粒子) / 解像度: 2.8 Å
化合物	ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose / N-アセチル-β-D-グルコサミン / N-アセチルグルコサミン ChemComp-CA: Unknown entry / カルシウムジカチオン ChemComp-LPE: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE / O-(1-O-オクタデシル-L-グリセロ-3-ホスホ)コリン ChemComp-Y01: CHOLESTEROL HEMISUCCINATE / コレステリルヘミスクシナ-ト化合物画像なし ChemComp-JL3: Unknown entry PDB-1ahh: 7 ALPHA-HYDROXYSTEROID DEHYDROGENASE COMPLEXED WITH NAD+ PDB-1ahi: 7 ALPHA-HYDROXYSTEROID DEHYDROGENASE COMPLEXED WITH NADH AND 7-OXO GLYCOCHENODEOXYCHOLIC ACID PDB-1ahj: NITRILE HYDRATASE PDB-1ahk: DER F 2, THE MAJOR MITE ALLERGEN FROM DERMATOPHAGOIDES FARINAE, NMR, MINIMIZED AVERAGE STRUCTURE
由来	homo sapiens (ヒト)
キーワード	TRANSPORT PROTEIN (運搬体タンパク質) / Cav3.2 / voltage gated calcium channel (電位依存性カルシウムチャネル) / cryo-EM (低温電子顕微鏡法) / TTA-A2 / TTA-P2 / ML218 / ACT-709478