4PYW

1.92 angstrom crystal structure of A1AT:TTAI ternary complex

Summary for 4PYW

• Entry DOI: 10.2210/pdb4pyw/pdb
• Descriptor: Alpha-1-antitrypsin, ACE-THR-THR-ALA-ILE-NH2, GLYCEROL, ... (4 entities in total)
• Functional Keywords: serpin, hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted. Short peptide from AAT: Secreted, extracellular space, extracellular matrix: P01009
• Total number of polymer chains: 3
• Total formula weight: 46652.94

Authors

Nyon, M.P.,Day, J.,Gooptu, B. (deposition date: 2014-03-28, release date: 2015-06-10, Last modification date: 2024-10-30)

Primary citation

Nyon, M.P.,Prentice, T.,Day, J.,Kirkpatrick, J.,Sivalingam, G.N.,Levy, G.,Haq, I.,Irving, J.A.,Lomas, D.A.,Christodoulou, J.,Gooptu, B.,Thalassinos, K.
An integrative approach combining ion mobility mass spectrometry, X-ray crystallography, and nuclear magnetic resonance spectroscopy to study the conformational dynamics of alpha 1 -antitrypsin upon ligand binding.
Protein Sci., 24:1301-1312, 2015

PubMed 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 (α1 -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 α1 -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 α1 -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 α1 -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.

PubMed: 26011795
DOI: 10.1002/pro.2706

Experimental method

X-RAY DIFFRACTION (1.91 Å)