Skip to main content
Home
Department Of Physics text logo
  • Research
    • Our research
    • Our research groups
    • Our research in action
    • Research funding support
    • Summer internships for undergraduates
  • Study
    • Undergraduates
    • Postgraduates
  • Engage
    • For alumni
    • For business
    • For schools
    • For the public
Menu
CMP
Credit: Jack Hobhouse

Peter Proks

Postdoctoral Research Assistant

Sub department

  • Condensed Matter Physics
peter.proks@physics.ox.ac.uk
Telephone: 72426
Clarendon Laboratory, room 071.4 & 071.7
  • About
  • Publications

Functional analysis of a structural model of the ATP-binding site of the KATP channel Kir6.2 subunit.

EMBO J 24:2 (2005) 229-239

Authors:

Jennifer F Antcliff, Shozeb Haider, Peter Proks, Mark SP Sansom, Frances M Ashcroft

Abstract:

ATP-sensitive potassium (KATP) channels couple cell metabolism to electrical activity by regulating K+ flux across the plasma membrane. Channel closure is mediated by ATP, which binds to the pore-forming subunit (Kir6.2). Here we use homology modelling and ligand docking to construct a model of the Kir6.2 tetramer and identify the ATP-binding site. The model is consistent with a large amount of functional data and was further tested by mutagenesis. Ligand binding occurs at the interface between two subunits. The phosphate tail of ATP interacts with R201 and K185 in the C-terminus of one subunit, and with R50 in the N-terminus of another; the N6 atom of the adenine ring interacts with E179 and R301 in the same subunit. Mutation of residues lining the binding pocket reduced ATP-dependent channel inhibition. The model also suggests that interactions between the C-terminus of one subunit and the 'slide helix' of the adjacent subunit may be involved in ATP-dependent gating. Consistent with a role in gating, mutations in the slide helix bias the intrinsic channel conformation towards the open state.
More details from the publisher
More details

Modelling of the ATP-inhibitory mechanism in ATP-sensitive potassium (KATP) channels: Insights from computer simulations of wild-type and mutant channels.

BIOPHYS J 88:1 (2005) 284A-284A

Authors:

LJ Shang, P Tammaro, SJ Tucker, P Proks
More details

A KCNJ11 mutation in the ATP-binding site of the KATP channel causes neonatal diabetes with epilepsy

DIABETOLOGIA 48 (2005) A113-A113

Authors:

K Shimomura, C Girard, P Proks, F Cerutti, R Lorini, F Barbetti, F Ashcroft
More details

Molecular basis of Kir6.2 mutations causing neonatal diabetes and neonatal diabetes with neurological features

BIOPHYSICAL JOURNAL 88:1 (2005) 181A-181A

Authors:

P Proks, JF Antcliff, AL Gloyn, AT Hattersley, FM Ashcroft
More details

Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features.

Proc Natl Acad Sci U S A 101:50 (2004) 17539-17544

Authors:

Peter Proks, Jennifer F Antcliff, Jon Lippiat, Anna L Gloyn, Andrew T Hattersley, Frances M Ashcroft

Abstract:

Inwardly rectifying potassium channels (Kir channels) control cell membrane K(+) fluxes and electrical signaling in diverse cell types. Heterozygous mutations in the human Kir6.2 gene (KCNJ11), the pore-forming subunit of the ATP-sensitive (K(ATP)) channel, cause permanent neonatal diabetes mellitus (PNDM). For some mutations, PNDM is accompanied by marked developmental delay, muscle weakness, and epilepsy (severe disease). To determine the molecular basis of these different phenotypes, we expressed wild-type or mutant (R201C, Q52R, or V59G) Kir6.2/sulfonylurea receptor 1 channels in Xenopus oocytes. All mutations increased resting whole-cell K(ATP) currents by reducing channel inhibition by ATP, but, in the simulated heterozygous state, mutations causing PNDM alone (R201C) produced smaller K(ATP) currents and less change in ATP sensitivity than mutations associated with severe disease (Q52R and V59G). This finding suggests that increased K(ATP) currents hyperpolarize pancreatic beta cells and impair insulin secretion, whereas larger K(ATP) currents are required to influence extrapancreatic cell function. We found that mutations causing PNDM alone impair ATP sensitivity directly (at the binding site), whereas those associated with severe disease act indirectly by biasing the channel conformation toward the open state. The effect of the mutation on ATP sensitivity in the heterozygous state reflects the different contributions of a single subunit in the Kir6.2 tetramer to ATP inhibition and to the energy of the open state. Our results also show that mutations in the slide helix of Kir6.2 (V59G) influence the channel kinetics, providing evidence that this domain is involved in Kir channel gating, and suggest that the efficacy of sulfonylurea therapy in PNDM may vary with genotype.
More details from the publisher
More details

Pagination

  • First page First
  • Previous page Prev
  • …
  • Page 10
  • Page 11
  • Page 12
  • Page 13
  • Current page 14
  • Page 15
  • Page 16
  • Page 17
  • Page 18
  • …
  • Next page Next
  • Last page Last

Footer Menu

  • Contact us
  • Giving to the Dept of Physics
  • Work with us
  • Media

User account menu

  • Log in

Follow us

FIND US

Clarendon Laboratory,

Parks Road,

Oxford,

OX1 3PU

CONTACT US

Tel: +44(0)1865272200

University of Oxfrod logo Department Of Physics text logo
IOP Juno Champion logo Athena Swan Silver Award logo

© University of Oxford - Department of Physics

Cookies | Privacy policy | Accessibility statement

Built by: Versantus

  • Home
  • Research
  • Study
  • Engage
  • Our people
  • News & Comment
  • Events
  • Our facilities & services
  • About us
  • Current students
  • Staff intranet