4pyw
1.92 angstrom crystal structure of A1AT:TTAI ternary complex
Structural highlights
DiseaseA1AT_HUMAN Defects in SERPINA1 are the cause of alpha-1-antitrypsin deficiency (A1ATD) [MIM:613490. A disorder whose most common manifestation is emphysema, which becomes evident by the third to fourth decade. A less common manifestation of the deficiency is liver disease, which occurs in children and adults, and may result in cirrhosis and liver failure. Environmental factors, particularly cigarette smoking, greatly increase the risk of emphysema at an earlier age.[1] [2] [3] FunctionA1AT_HUMAN Inhibitor of serine proteases. Its primary target is elastase, but it also has a moderate affinity for plasmin and thrombin. Irreversibly inhibits trypsin, chymotrypsin and plasminogen activator. The aberrant form inhibits insulin-induced NO synthesis in platelets, decreases coagulation time and has proteolytic activity against insulin and plasmin.[:][4] [5] Short peptide from AAT: reversible chymotrypsin inhibitor. It also inhibits elastase, but not trypsin. Its major physiological function is the protection of the lower respiratory tract against proteolytic destruction by human leukocyte elastase (HLE).[:][6] [7] Publication Abstract from PubMedNative 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 (alpha1 -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 alpha1 -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 alpha1 -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 alpha1 -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. An integrative approach combining ion mobility mass spectrometry, X-ray crystallography and NMR spectroscopy to study the conformational dynamics of alpha -antitrypsin upon ligand binding.,Nyon MP, Prentice T, Day J, Kirkpatrick J, Sivalingam GN, Levy G, Haq I, Irving JA, Lomas DA, Christodoulou J, Gooptu B, Thalassinos K Protein Sci. 2015 May 26. doi: 10.1002/pro.2706. PMID:26011795[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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