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Does glutamine methylation affect the intrinsic conformation of the universally conserved GGQ motif in ribosomal release factors?
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
2009 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 48, no 15, 3483-3489 p.Article in journal (Refereed) Published
Abstract [en]

The GGQ motif is the only universally conserved feature of ribosomal class 1 release factors. Mutational experiments and structural studies have suggested that the glutamine residue of the GGQ motif Q 185 in human eRF1 numbering) is critical for catalysis of the termination   reaction on the ribosome. Furthermore, it has been established that Q185 is NE methylated in prokaryotes as well as eukaryotes, and that methylation significantly enhances the catalytic activity. It is, however, not known whether this methylation affects the intrinsic   structure of the free release factor, which could be important for its interaction with the ribosome. In this work, we report molecular dynamics simulations, starting from 25 different NMR structures of human eRF1, in addressing this problem. The results show that there is   no such structural effect on the free release factor caused by the NE methylation of Q185, suggesting that its role is intimately associated with the ribosome environment.

Place, publisher, year, edition, pages
Washington, DC, USA: American Chemical Society , 2009. Vol. 48, no 15, 3483-3489 p.
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-101411DOI: 10.1021/bi900117rISI: 000265170200025OAI: oai:DiVA.org:uu-101411DiVA: diva2:212964
Available from: 2009-04-26 Created: 2009-04-26 Last updated: 2010-08-02Bibliographically approved
In thesis
1. Computational Analysis of Molecular Recognition Involving the Ribosome and a Voltage Gated K+ Channel
Open this publication in new window or tab >>Computational Analysis of Molecular Recognition Involving the Ribosome and a Voltage Gated K+ Channel
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Over the last few decades, computer simulation techniques have been established as an essential tool for understanding biochemical processes. This thesis deals mainly with the application of free energy calculations to ribosomal complexes and a cardiac ion channel.

The linear interaction energy (LIE) method is used to explore the energetic properties of the essential process of codon–anticodon recognition on the ribosome. The calculations show the structural and energetic consequences and effects of first, second, and third position mismatches in the ribosomal decoding center.

Recognition of stop codons by ribosomal termination complexes is fundamentally different from sense codon recognition. Free energy perturbation simulations are used to study the detailed energetics of stop codon recognition by the bacterial ribosomal release factors RF1 and RF2. The calculations explain the vastly different responses to third codon position A to G substitutions by RF1 and RF2. Also, previously unknown highly specific water interactions are identified.

The GGQ loop of ribosomal RFs is essential for its hydrolytic activity and contains a universally methylated glutamine residue. The structural effect of this methylation is investigated. The results strongly suggest that the methylation has no effect on the intrinsic conformation of the GGQ loop, and, thus, that its sole purpose is to enhance interactions in the ribosomal termination complex.

A first microscopic, atomic level, analysis of blocker binding to the pharmaceutically interesting potassium ion channel Kv1.5 is presented. A previously unknown uniform binding mode is identified, and experimental binding data is accurately reproduced. Furthermore, problems associated with pharmacophore models based on minimized gas phase ligand conformations are highlighted.

Generalized Born and Poisson–Boltzmann continuum models are incorporated into the LIE method to enable implicit treatment of solvent, in an effort to improve speed and convergence. The methods are evaluated and validated using a set of plasmepsin II inhibitors.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 649
Keyword
computer simulations, molecular dynamics, ligand binding, binding free energy, linear interaction energy, codon recognition, translation termination, release factor, voltage gated potassium ion channel, Kv1.5
National Category
Structural Biology Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:uu:diva-101413 (URN)978-91-554-7539-0 (ISBN)
Public defence
2009-06-12, B41, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2009-05-20 Created: 2009-04-26 Last updated: 2010-01-13Bibliographically approved

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Andér, Martin

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