1QMB

Cleaved alpha-1-antitrypsin polymer

Summary for 1QMB

• Entry DOI: 10.2210/pdb1qmb/pdb
• Related: 1ATU 1KCT 1PSI 2PSI 7API 8API 9API
• Descriptor: ALPHA-1-ANTITRYPSIN (3 entities in total)
• Functional Keywords: serine protease inhibitor, serpin, antitrypsin, polymer, cleaved
• Biological source: HOMO SAPIENS; More
• Cellular location: Secreted. Short peptide from AAT: Secreted, extracellular space, extracellular matrix: P01009 P01009
• Total number of polymer chains: 2
• Total formula weight: 41386.39

Authors

Huntington, J.A.,Pannu, N.S.,Hazes, B.,Read, R.J.,Lomas, D.A.,Carrell, R.W. (deposition date: 1999-09-24, release date: 2000-02-06, Last modification date: 2023-12-13)

Primary citation

Huntington, J.A.,Pannu, N.S.,Hazes, B.,Read, R.J.,Lomas, D.A.,Carrell, R.W.
A 2.6A Structure of a Serpin Polymer and Implications for Conformational Disease
J.Mol.Biol., 293:449-, 1999

PubMed Abstract: The function of the serpins as proteinase inhibitors depends on their ability to insert the cleaved reactive centre loop as the fourth strand in the main A beta-sheet of the molecule upon proteolytic attack at the reactive centre, P1-P1'. This mechanism is vulnerable to mutations which result in inappropriate intra- or intermolecular loop insertion in the absence of cleavage. Intermolecular loop insertion is known as serpin polymerisation and results in a variety of diseases, most notably liver cirrhosis resulting from mutations of the prototypical serpin alpha1-antitrypsin. We present here the 2.6 A structure of a polymer of alpha1-antitrypsin cleaved six residues N-terminal to the reactive centre, P7-P6 (Phe352-Leu353). After self insertion of P14 to P7, intermolecular linkage is affected by insertion of the P6-P3 residues of one molecule into the partially occupied beta-sheet A of another. This results in an infinite, linear polymer which propagates in the crystal along a 2-fold screw axis. These findings provide a framework for understanding the uncleaved alpha1-antitrypsin polymer and fibrillar and amyloid deposition of proteins seen in other conformational diseases, with the ordered array of polymers in the crystal resulting from slow accretion of the cleaved serpin over the period of a year.

PubMed: 10543942
DOI: 10.1006/JMBI.1999.3184

Experimental method

X-RAY DIFFRACTION (2.6 Å)