The Structural Basis for the Binding of Repaglinide to the Pancreatic KATP Channel

Ding, Dian; Wang, Mengmeng; Wu, Jing-Xiang; Kang, Yimin; Chen, Lei

doi:10.1016/j.celrep.2019.04.050

Cited by 87 publications

(140 citation statements)

References 56 publications

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“…While this paper was in review, a paper has been published by Ding et al showing a structure of a K ATP channel formed by a SUR1-Kir6.2 fusion protein bound to repaglinide (Ding et al, 2019).…”

Section: Methodsmentioning

confidence: 99%

Mechanism of pharmacochaperoning in a mammalian KATP channel revealed by cryo-EM

Martin

Sung

Yang

et al. 2019

eLife

131

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ATP-sensitive potassium (KATP) channels composed of a pore-forming Kir6.2 potassium channel and a regulatory ABC transporter sulfonylurea receptor 1 (SUR1) regulate insulin secretion in pancreatic β-cells to maintain glucose homeostasis. Mutations that impair channel folding or assembly prevent cell surface expression and cause congenital hyperinsulinism. Structurally diverse KATP inhibitors are known to act as pharmacochaperones to correct mutant channel expression, but the mechanism is unknown. Here, we compare cryoEM structures of a mammalian KATP channel bound to pharmacochaperones glibenclamide, repaglinide, and carbamazepine. We found all three drugs bind within a common pocket in SUR1. Further, we found the N-terminus of Kir6.2 inserted within the central cavity of the SUR1 ABC core, adjacent the drug binding pocket. The findings reveal a common mechanism by which diverse compounds stabilize the Kir6.2 N-terminus within SUR1’s ABC core, allowing it to act as a firm ‘handle’ for the assembly of metastable mutant SUR1-Kir6.2 complexes.

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Section: Methodsmentioning

confidence: 99%

Mechanism of pharmacochaperoning in a mammalian KATP channel revealed by cryo-EM

Martin

Sung

Yang

et al. 2019

eLife

131

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“…This loop is adjacent to the inhibitory nucleotide-binding site on Kir6.2 and the interface between neighbouring Kir6.2 subunits. Mutations at K205 were previously shown to reduce sensitivity of KATP to nucleotide-dependent inhibition (Pratt et al, 2012;Ding et al, 2019). Other mutations in L0 are associated with neonatal diabetes (Ashcroft et al, 2017) and PHHI (Snider et al, 2013).…”

Section: Kir62-c166s Affects the Ability Of Bound Nucleotides To Clomentioning

confidence: 99%

Nucleotide inhibition of the pancreatic ATP-sensitive K+ channel explored with patch-clamp fluorometry

Usher

Ashcroft

Puljung

2019

Preprint

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Pancreatic ATP-sensitive K + channels (KATP) comprise four inward rectifier subunits (Kir6.2), each associated with a sulphonylurea receptor (SUR1). ATP/ADP binding to Kir6.2 shuts KATP.Mg-nucleotide binding to SUR1 stimulates KATP. In the absence of Mg 2+ , SUR1 increases the apparent affinity for nucleotide inhibition at Kir6.2 by an unknown mechanism. We simultaneously measured channel currents and nucleotide binding to Kir6.2. Fits to combined data sets suggest that KATP closes with only one nucleotide molecule bound. A Kir6.2 mutation (C166S) that increases channel activity did not affect nucleotide binding, but greatly perturbed the ability of bound nucleotide to inhibit KATP. Mutations at position K205 in SUR1 affected both nucleotide affinity and the ability of bound nucleotide to inhibit KATP. This suggests a dual role for SUR1 in KATP inhibition, both in directly contributing to nucleotide binding and in stabilising the nucleotidebound closed state.

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“…drugs, lipids or peptides). However, the type I exporter fold has evolved to fulfill a myriad of additional functionalities and is found in the incarnation of a nucleotide-gated chloride channel (CFTR) [48], a nucleotide-sensing regulatory domain of a potassium channel (SUR1) [49,50], and importer proteins for cobalamin (ABCD4 [51] and Rv1819c [52]) or bacterial siderophores (IrtAB) [53]. Compared with ABC importers, classical ABC exporters are rather simple proteins.…”

Section: Structural and Functional Diversity Of Abc Exportersmentioning

confidence: 99%

Structures of ABC transporters: handle with care

2020

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In the past two decades, the ATP-binding cassette (ABC) transporters' field has undergone a structural revolution. The importance of structural biology to the development of the field of ABC transporters cannot be overstated, as the ensemble of structures not only revealed the architecture of ABC transporters but also shaped our mechanistic view of these remarkable molecular machines. Nevertheless, we advocate that the mechanistic interpretation of the structures is not trivial and should be carried out with prudence. Herein, we bring several examples of structures of ABC transporters that merit re-interpretation via careful comparison to experimental data. We propose that it is of the upmost importance to place new structures within the context of the available experimental data.

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The Structural Basis for the Binding of Repaglinide to the Pancreatic KATP Channel

Cited by 87 publications

References 56 publications

Mechanism of pharmacochaperoning in a mammalian KATP channel revealed by cryo-EM

Mechanism of pharmacochaperoning in a mammalian KATP channel revealed by cryo-EM

Nucleotide inhibition of the pancreatic ATP-sensitive K+ channel explored with patch-clamp fluorometry

Structures of ABC transporters: handle with care

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