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Molecular structure of human KATP in complex with ATP and ADP.

Lee KPK, Chen J, MacKinnon R
Elife 6 (2017)
Cited: 82 times
EuropePMC logo PMID: 29286281

Abstract

In many excitable cells, KATP channels respond to intracellular adenosine nucleotides: ATP inhibits while ADP activates. We present two structures of the human pancreatic KATP channel, containing the ABC transporter SUR1 and the inward-rectifier K+ channel Kir6.2, in the presence of Mg2+ and nucleotides. These structures, referred to as quatrefoil and propeller forms, were determined by single-particle cryo-EM at 3.9 Å and 5.6 Å, respectively. In both forms, ATP occupies the inhibitory site in Kir6.2. The nucleotide-binding domains of SUR1 are dimerized with Mg2+-ATP in the degenerate site and Mg2+-ADP in the consensus site. A lasso extension forms an interface between SUR1 and Kir6.2 adjacent to the ATP site in the propeller form and is disrupted in the quatrefoil form. These structures support the role of SUR1 as an ADP sensor and highlight the lasso extension as a key regulatory element in ADP's ability to override ATP inhibition.

Reviews - 6c3p mentioned but not cited (6)

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Articles - 6c3p mentioned but not cited (14)

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  10. Integrative Study of the Structural and Dynamical Properties of a KirBac3.1 Mutant: Functional Implication of a Highly Conserved Tryptophan in the Transmembrane Domain. Fagnen C, Bannwarth L, Oubella I, Zuniga D, Haouz A, Forest E, Scala R, Bendahhou S, De Zorzi R, Perahia D, Vénien-Bryan C. Int J Mol Sci 23 335 (2021)
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  12. Palmitoylation of the KATP channel Kir6.2 subunit promotes channel opening by regulating PIP2 sensitivity. Yang HQ, Martinez-Ortiz W, Hwang J, Fan X, Cardozo TJ, Coetzee WA. Proc Natl Acad Sci U S A 117 10593-10602 (2020)
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  14. Structural Insights into ATP-Sensitive Potassium Channel Mechanics: A Role of Intrinsically Disordered Regions. Walczewska-Szewc K, Nowak W. J Chem Inf Model 63 1806-1818 (2023)


Reviews citing this publication (21)

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  7. New insights into KATP channel gene mutations and neonatal diabetes mellitus. Pipatpolkai T, Usher S, Stansfeld PJ, Ashcroft FM. Nat Rev Endocrinol 16 378-393 (2020)
  8. Kir6.1 and SUR2B in Cantú syndrome. McClenaghan C, Nichols CG. Am J Physiol Cell Physiol 323 C920-C935 (2022)
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  13. Towards the Idea of Molecular Brains. Timsit Y, Grégoire SP. Int J Mol Sci 22 11868 (2021)
  14. Channelopathy Genes in Pulmonary Arterial Hypertension. Welch CL, Chung WK. Biomolecules 12 265 (2022)
  15. Contribution of Mitochondria to Insulin Secretion by Various Secretagogues. Ježek P, Holendová B, Jabůrek M, Dlasková A, Plecitá-Hlavatá L. Antioxid Redox Signal 36 920-952 (2022)
  16. Implication of Potassium Channels in the Pathophysiology of Pulmonary Arterial Hypertension. Le Ribeuz H, Capuano V, Girerd B, Humbert M, Montani D, Antigny F. Biomolecules 10 (2020)
  17. Ion Transporters, Channelopathies, and Glucose Disorders. Demirbilek H, Galcheva S, Vuralli D, Al-Khawaga S, Hussain K. Int J Mol Sci 20 (2019)
  18. KATP channel mutations in congenital hyperinsulinism: Progress and challenges towards mechanism-based therapies. ElSheikh A, Shyng SL. Front Endocrinol (Lausanne) 14 1161117 (2023)
  19. Potassium Channels as Therapeutic Targets in Pulmonary Arterial Hypertension. Redel-Traub G, Sampson KJ, Kass RS, Bohnen MS. Biomolecules 12 1341 (2022)
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  21. Targeting receptor complexes: a new dimension in drug discovery. Rosenbaum MI, Clemmensen LS, Bredt DS, Bettler B, Strømgaard K. Nat Rev Drug Discov 19 884-901 (2020)

Articles citing this publication (41)

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  2. Ameliorative Effect of Ocimum forskolei Benth on Diabetic, Apoptotic, and Adipogenic Biomarkers of Diabetic Rats and 3T3-L1 Fibroblasts Assisted by In Silico Approach. Khalil HE, Abdelwahab MF, Emeka PM, Badger-Emeka LI, Thirugnanasambantham K, Ibrahim HM, Naguib SM, Matsunami K, Abdel-Wahab NM. Molecules 27 2800 (2022)
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  5. ATP binding without hydrolysis switches sulfonylurea receptor 1 (SUR1) to outward-facing conformations that activate KATP channels. Sikimic J, McMillen TS, Bleile C, Dastvan F, Quast U, Krippeit-Drews P, Drews G, Bryan J. J Biol Chem 294 3707-3719 (2019)
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  18. Insights on the structure-function relationship of human multidrug resistance protein 7 (MRP7/ABCC10) from molecular dynamics simulations and docking studies. Wang JQ, Cui Q, Lei ZN, Teng QX, Ji N, Lin L, Liu Z, Chen ZS. MedComm (2020) 2 221-235 (2021)
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  24. Sulfonylurea-Insensitive Permanent Neonatal Diabetes Caused by a Severe Gain-of-Function Tyr330His Substitution in Kir6.2. McClenaghan C, Rapini N, De Rose DU, Gao J, Roeglin J, Bizzarri C, Schiaffini R, Tiberi E, Mucciolo M, Deodati A, Perri A, Vento G, Barbetti F, Nichols CG, Cianfarani S. Horm Res Paediatr 95 215-223 (2022)
  25. Temporal Lobe Epilepsy, Stroke, and Traumatic Brain Injury: Mechanisms of Hyperpolarized, Depolarized, and Flow-Through Ion Channels Utilized as Tri-Coordinate Biomarkers of Electrophysiologic Dysfunction. Sizemore G, Lucke-Wold B, Rosen C, Simpkins JW, Bhatia S, Sun D. OBM Neurobiol 2 (2018)
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