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TitleThe Structural Basis for the Binding of Repaglinide to the Pancreatic K Channel.
Journal, issue, pagesCell Rep, Vol. 27, Issue 6, Page 1848-11857.e4, Year 2019
Publish dateMay 7, 2019
AuthorsDian Ding / Mengmeng Wang / Jing-Xiang Wu / Yunlu Kang / Lei Chen /
PubMed AbstractRepaglinide (RPG) is a short-acting insulin secretagogue widely prescribed for the treatment of type 2 diabetes. It boosts insulin secretion by inhibiting the pancreatic ATP-sensitive potassium ...Repaglinide (RPG) is a short-acting insulin secretagogue widely prescribed for the treatment of type 2 diabetes. It boosts insulin secretion by inhibiting the pancreatic ATP-sensitive potassium channel (K). However, the mechanisms by which RPG binds to the K channel are poorly understood. Here, we describe two cryo-EM structures: the pancreatic K channel in complex with inhibitory RPG and adenosine-5'-(γ-thio)-triphosphate (ATPγS) at 3.3 Å and a medium-resolution structure of a RPG-bound mini SUR1 protein in which the N terminus of the inward-rectifying potassium channel 6.1 (Kir6.1) is fused to the ABC transporter module of the sulfonylurea receptor 1 (SUR1). These structures reveal the binding site of RPG in the SUR1 subunit. Furthermore, the high-resolution structure reveals the complex architecture of the ATP binding site, which is formed by both Kir6.2 and SUR1 subunits, and the domain-domain interaction interfaces.
External linksCell Rep / PubMed:31067468
MethodsEM (single particle)
Resolution3.3 - 6.45 Å
Structure data

9787

6jb1

EMDB-9787, PDB-6jb1:
Structure of pancreatic ATP-sensitive potassium channel bound with repaglinide and ATPgammaS at 3.3A resolution
Method: EM (single particle) / Resolution: 3.3 Å

9788

6jb3

EMDB-9788, PDB-6jb3:
Structure of SUR1 subunit bound with repaglinide
Method: EM (single particle) / Resolution: 3.53 Å

EMDB-9789:
Structure of a SUR1 fusion protein
Method: EM (single particle) / Resolution: 6.45 Å

Chemicals

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM / POPC

ChemComp-AGS:
PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-gamma-S, energy-carrying molecule analogue*YM

ChemComp-AJP:
Digitonin / detergent*YM / Digitonin

ChemComp-BJX:
Repaglinide / medication*YM / Repaglinide

ChemComp-PTY:
PHOSPHATIDYLETHANOLAMINE / phospholipid*YM / Phosphatidylethanolamine

Source
  • mus musculus (house mouse)
  • mesocricetus auratus (golden hamster)
KeywordsMEMBRANE PROTEIN / KATP / channel / repaglinide / Kir / ABC transporter / SUR / diabetes / insulin secretagogue

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