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Structure paper

TitleMolecular basis for ligand activation of the human KCNQ2 channel.
Journal, issue, pagesCell Res, Vol. 31, Issue 1, Page 52-61, Year 2021
Publish dateSep 3, 2020
AuthorsXiaoxiao Li / Qiansen Zhang / Peipei Guo / Jie Fu / Lianghe Mei / Dashuai Lv / Jiangqin Wang / Dongwu Lai / Sheng Ye / Huaiyu Yang / Jiangtao Guo /
PubMed AbstractThe voltage-gated potassium channel KCNQ2 is responsible for M-current in neurons and is an important drug target to treat epilepsy, pain and several other diseases related to neuronal hyper- ...The voltage-gated potassium channel KCNQ2 is responsible for M-current in neurons and is an important drug target to treat epilepsy, pain and several other diseases related to neuronal hyper-excitability. A list of synthetic compounds have been developed to directly activate KCNQ2, yet our knowledge of their activation mechanism is limited, due to lack of high-resolution structures. Here, we report cryo-electron microscopy (cryo-EM) structures of the human KCNQ2 determined in apo state and in complex with two activators, ztz240 or retigabine, which activate KCNQ2 through different mechanisms. The activator-bound structures, along with electrophysiology analysis, reveal that ztz240 binds at the voltage-sensing domain and directly stabilizes it at the activated state, whereas retigabine binds at the pore domain and activates the channel by an allosteric modulation. By accurately defining ligand-binding sites, these KCNQ2 structures not only reveal different ligand recognition and activation mechanisms, but also provide a structural basis for drug optimization and design.
External linksCell Res / PubMed:32884139 / PubMed Central
MethodsEM (single particle)
Resolution3.1 - 3.9 Å
Structure data

30443

7cr0

EMDB-30443, PDB-7cr0:
human KCNQ2 in apo state
Method: EM (single particle) / Resolution: 3.1 Å

30444

7cr1

EMDB-30444, PDB-7cr1:
human KCNQ2 in complex with ztz240
Method: EM (single particle) / Resolution: 3.4 Å

30445

7cr2

EMDB-30445, PDB-7cr2:
human KCNQ2 in complex with retigabine
Method: EM (single particle) / Resolution: 3.2 Å

30446

7cr3

EMDB-30446, PDB-7cr3:
human KCNQ2-CaM in apo state
Method: EM (single particle) / Resolution: 3.6 Å

30447

7cr4

EMDB-30447, PDB-7cr4:
human KCNQ2-CaM in complex with ztz240
Method: EM (single particle) / Resolution: 3.9 Å

30448

7cr7

EMDB-30448, PDB-7cr7:
human KCNQ2-CaM in complex with retigabine
Method: EM (single particle) / Resolution: 3.7 Å

Chemicals

ChemComp-GB9:
N-(6-chloranylpyridin-3-yl)-4-fluoranyl-benzamide

ChemComp-FBX:
ethyl N-[2-azanyl-4-[(4-fluorophenyl)methylamino]phenyl]carbamate / Retigabine

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / ion channel

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