NDLI: An integrative approach combining ion mobility mass spectrometry, X-ray crystallography, and nuclear magnetic resonance spectroscopy to study the conformational dynamics of 1 -antitrypsin upon ligand binding.

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An integrative approach combining ion mobility mass spectrometry, X-ray crystallography, and nuclear magnetic resonance spectroscopy to study the conformational dynamics of 1 -antitrypsin upon ligand binding.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Haq, Imran Christodoulou, John Thalassinos, Konstantinos Sivalingam, Ganesh N. Irving, James A. Prentice, Tanya Levy, Geraldine Lomas, David A. Gooptu, Bibek Day, Jemma Nyon, Mun Peak Kirkpatrick, John
Description	Country affiliation: United kingdom Author Affiliation: Nyon MP ( Institute of Structural and Molecular Biology, Division of Biosciences, Division of Biosciences, University College London, London, WC1E 6BT, United Kingdom.); Prentice T ( Institute of Structural and Molecular Biology, Division of Biosciences, Division of Biosciences, University College London, London, WC1E 6BT, United Kingdom.); Day J ( Institute of Structural and Molecular Biology, Division of Biosciences, Division of Biosciences, University College London, London, WC1E 6BT, United Kingdom.); Kirkpatrick J ( Institute of Structural and Molecular Biology, Division of Biosciences, Division of Biosciences, University College London, London, WC1E 6BT, United Kingdom.); Sivalingam GN ( Institute of Structural and Molecular Biology, Division of Biosciences, Division of Biosciences, University College London, London, WC1E 6BT, United Kingdom.); Levy G ( Institute of Structural and Molecular Biology, Division of Biosciences, Division of Biosciences, University College London, London, WC1E 6BT, United Kingdom.); Haq I ( Wolfson Institute for Biomedical Research, Division of Medicine, University College London, London, WC1E 6BT, United Kingdom.); Irving JA ( Wolfson Institute for Biomedical Research, Division of Medicine, University College London, London, WC1E 6BT, United Kingdom.); Lomas DA ( Wolfson Institute for Biomedical Research, Division of Medicine, University College London, London, WC1E 6BT, United Kingdom.); Christodoulou J ( Institute of Structural and Molecular Biology, Division of Biosciences, Division of Biosciences, University College London, London, WC1E 6BT, United Kingdom.); Gooptu B ( Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, University of London, London, WC1E 7HX, United Kingdom.); Thalassinos K ( Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, University of London, London, WC1E 7HX, United Kingdom.)
Abstract	Native mass spectrometry (MS) methods permit the study of multiple protein species within solution equilibria, whereas ion mobility (IM)-MS can report on conformational behavior of specific states. We used IM-MS to study a conformationally labile protein ( 1 -antitrypsin) that undergoes pathological polymerization in the context of point mutations. The folded, native state of the Z-variant remains highly polymerogenic in physiological conditions despite only minor thermodynamic destabilization relative to the wild-type variant. Various data implicate kinetic instability (conformational lability within a native state ensemble) as the basis of Z 1 -antitrypsin polymerogenicity. We show the ability of IM-MS to track such disease-relevant conformational behavior in detail by studying the effects of peptide binding on 1 -antitrypsin conformation and dynamics. IM-MS is, therefore, an ideal platform for the screening of compounds that result in therapeutically beneficial kinetic stabilization of native 1 -antitrypsin. Our findings are confirmed with high-resolution X-ray crystallographic and nuclear magnetic resonance spectroscopic studies of the same event, which together dissect structural changes from dynamic effects caused by peptide binding at a residue-specific level. IM-MS methods, therefore, have great potential for further study of biologically relevant thermodynamic and kinetic instability of proteins and provide rapid and multidimensional characterization of ligand interactions of therapeutic interest.
ISSN	09618368
e-ISSN	1469896X
DOI	10.1002/pro.2706
Journal	Protein Science
Issue Number	8
Volume Number	24
Language	English
Publisher	Wiley-Blackwell (on behalf of The Protein Society)
Publisher Date	2015-08-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Alpha 1-antitrypsin Chemistry Crystallography, X-ray Drug Discovery Ligands Mass Spectrometry Molecular Dynamics Simulation Mutation Nuclear Magnetic Resonance, Biomolecular Peptides Pharmacology Protein Binding Protein Conformation Thermodynamics Genetics Metabolism Research Support, Non-u.s. Gov't Discipline Biochemistry
Content Type	Text
Resource Type	Article
Subject	Medicine Molecular Biology Biochemistry

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