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Molecular determinants of snurportin 1 ligand affinity and structural response upon binding.

ABSTRACT: The transport of large biomolecules such as proteins and RNA across nuclear pore complexes is a field of strong interest and research. Although the basic mechanisms are fairly well understood, the details of the underlying intermolecular interaction within these transport complexes are still unclear. The recognition dynamics and energetics of cargo binding to the transport receptor are not yet resolved. Here, the binding of dimethylated RNA-caps to snurportin 1 is studied by molecular-dynamics simulations. The simulations reveal a strong structural response of the protein upon RNA-cap release. In particular, major rearrangements occur in regions already intrinsically flexible in the holo structure. Additionally, the difference in free energy of binding to snurportin 1 between the two methylation states of the RNA-cap, responsible for the directionality of the transport is quantified. In particular, desolvation of the ligand is revealed as the key-step in binding to snurportin 1. These findings suggest that the binding of m(3)G-capped RNA is mainly driven by the enhanced water entropy gain of the solvation shell.

SUBMITTER: Goette M

PROVIDER: S-EPMC2711343 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Molecular determinants of snurportin 1 ligand affinity and structural response upon binding.

Goette Maik M Stumpe Martin C MC Ficner Ralf R Grubmüller Helmut H

Biophysical journal 20090701 2

The transport of large biomolecules such as proteins and RNA across nuclear pore complexes is a field of strong interest and research. Although the basic mechanisms are fairly well understood, the details of the underlying intermolecular interaction within these transport complexes are still unclear. The recognition dynamics and energetics of cargo binding to the transport receptor are not yet resolved. Here, the binding of dimethylated RNA-caps to snurportin 1 is studied by molecular-dynamics s ...[more]

PMID: 19619473

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Project description:P2X receptors are trimeric eukaryotic ATP-gated cation channels. Extracellular ATP-their physiological ligand-is released as a neurotransmitter and in conditions of cell damage such as inflammation, and substantial evidence implicates P2X receptors in diseases including neuropathic pain, cancer, and arthritis. In 2009, the first P2X crystal structure, Danio rerio P2X4 in the apo- state, was published, and this was followed in 2012 by the ATP-bound structure. These structures transformed our understanding of the conformational changes induced by ATP binding and the mechanism of ligand specificity, and enabled homology modeling of mammalian P2X receptors for ligand docking and rational design of receptor modulators. P2X receptors are attractive drug targets, and a wide array of potent, subtype-selective modulators (mostly antagonists) have been developed. In 2016, crystal structures of human P2X3 in complex with the competitive antagonists TNP-ATP and A-317491, and Ailuropoda melanoleuca P2X7 in complex with a series of allosteric antagonists were published, giving fascinating insights into the mechanism of channel antagonism. In this article we not only summarize current understanding of small-molecule modulator binding at P2X receptors, but also use this information in combination with previously published structure-function data and molecular docking experiments, to hypothesize a role for the dorsal fin loop region in differential ATP potency, and describe novel, testable binding conformations for both the semi-selective synthetic P2X7 agonist 2'-(3')-O-(4-benzoyl)benzoyl ATP (BzATP), and the P2X4-selective positive allosteric modulator ivermectin. We find that the distal benzoyl group of BzATP lies in close proximity to Lys-127, a residue previously implicated in BzATP binding to P2X7, potentially explaining the increased potency of BzATP at rat P2X7 receptors. We also present molecular docking of ivermectin to rat P2X4 receptors, illustrating a plausible binding conformation between the first and second transmembrane domains which not only tallies with previous mutagenesis studies, but would also likely have the effect of stabilizing the open channel structure, consistent with the mode of action of this positive allosteric modulator. From our docking simulations and analysis of sequence homology we propose a series of mutations likely to confer ivermectin sensitivity to human P2X1.

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Molecular determinants of snurportin 1 ligand affinity and structural response upon binding.

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Molecular determinants of snurportin 1 ligand affinity and structural response upon binding.

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