[NMR paper] An integrative approach combining ion mobility mass spectrometry, X-ray crystallography and NMR spectroscopy to study the conformational dynamics of ?1 -antitrypsin upon ligand binding.
An integrative approach combining ion mobility mass spectrometry, X-ray crystallography and NMR spectroscopy to study the conformational dynamics of ?1 -antitrypsin upon ligand binding.
An integrative approach combining ion mobility mass spectrometry, X-ray crystallography and NMR spectroscopy to study the conformational dynamics of ?1 -antitrypsin upon ligand binding.
Protein Sci. 2015 May 26;
Authors: Nyon MP, Prentice T, Day J, Kirkpatrick J, Sivalingam GN, Levy G, Haq I, Irving JA, Lomas DA, Christodoulou J, Gooptu B, Thalassinos K
Abstract
Native mass spectrometry (MS) methods permit the study of multiple protein species within solution equilibria, whilst ion mobility (IM)-MS can report on conformational behaviour of specific states. We used IM-MS to study a conformationally labile protein (?1 -antitrypsin) that undergoes pathological polymerisation in the context of point mutations. The folded, native state of the Z variant remains highly polymerogenic in physiological conditions, despite only minor thermodynamic destabilisation 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 behaviour 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 stabilisation of native ?1 -antitrypsin. Our findings are confirmed with high resolution X-ray crystallographic and NMR 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 characterisation of ligand interactions of therapeutic interest. This article is protected by copyright. All rights reserved.
PMID: 26011795 [PubMed - as supplied by publisher]
An integrative approach combining ion mobility mass spectrometry, X-ray crystallography and NMR spectroscopy to study the conformational dynamics of ?1-antitrypsin upon ligand binding
An integrative approach combining ion mobility mass spectrometry, X-ray crystallography and NMR spectroscopy to study the conformational dynamics of ?1-antitrypsin upon ligand binding
Abstract
Native mass spectrometry (MS) methods permit the study of multiple protein species within solution equilibria, whilst ion mobility (IM)-MS can report on conformational behaviour of specific states. We used IM-MS to study a conformationally labile protein (?1-antitrypsin) that undergoes pathological polymerisation in the context of point mutations. The folded, native state of the Z variant remains...
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Quantitative comparison of structure and dynamics of elastin following three isolation schemes by 13C solid state NMR and MALDI mass spectrometry.
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Biochim Biophys Acta. 2015 Jan 12;
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Abstract
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PLoS One. 2013;8(9):e74040
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Abstract
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J Mass Spectrom. 2013 Aug;48(8):i
Authors: Santambrogio C, Favretto F, D'Onofrio M, Assfalg M, Grandori R, Molinari H
Abstract
Protein-ligand interactions are driven by many factors, including protein conformation and pH of the solution. Electrospray mass spectrometry can reveal the degree of protein folding from the distribution of...
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[NMR paper] Mass spectrometry and NMR analysis of ligand binding by human liver fatty acid binding protein.
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J Mass Spectrom. 2013 Aug;48(8):895-903
Authors: Santambrogio C, Favretto F, D'Onofrio M, Assfalg M, Grandori R, Molinari H
Abstract
Human liver fatty acid binding protein (hL-FABP) is the most abundant cytosolic protein in the liver. This protein plays important roles associated to partitioning of fatty acids (FAs) to specific...
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http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--pubs.acs.org-images-acspubs.jpg Related Articles Ligand binding alters the backbone mobility of intestinal fatty acid-binding protein as monitored by 15N NMR relaxation and 1H exchange.
Biochemistry. 1997 Feb 25;36(8):2278-90
Authors: Hodsdon ME, Cistola DP
The backbone dynamics of the liganded (holo) and unliganded (apo) forms of Escherichia...
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[NMR paper] Ligand binding alters the backbone mobility of intestinal fatty acid-binding protein
Ligand binding alters the backbone mobility of intestinal fatty acid-binding protein as monitored by 15N NMR relaxation and 1H exchange.
http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--pubs.acs.org-images-acspubs.jpg Related Articles Ligand binding alters the backbone mobility of intestinal fatty acid-binding protein as monitored by 15N NMR relaxation and 1H exchange.
Biochemistry. 1997 Feb 25;36(8):2278-90
Authors: Hodsdon ME, Cistola DP
The backbone dynamics of the liganded (holo) and unliganded (apo) forms of Escherichia...
An integrative approach combining ion mobility mass spectrometry, X-ray crystallography and NMR spectroscopy to study the conformational dynamics of ?1 -antitrypsin upon ligand binding.
Linear Mode
