5IO1
CRYSTAL STRUCTURE OF RECOMBINANT HUMAN Z ALPHA-1-ANTITRYPSIN
Summary for 5IO1
| Entry DOI | 10.2210/pdb5io1/pdb |
| Descriptor | Alpha-1-antitrypsin, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total) |
| Functional Keywords | serpins, acute phase, alternative splicing, blood coagulation, disease mutation, glycoprotein, hydrolase, polymorphism, protease, protease inhibitor, secreted, serine protease inhibitor, hydrolase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 90462.75 |
| Authors | Zhou, A. (deposition date: 2016-03-08, release date: 2016-06-08, Last modification date: 2024-10-30) |
| Primary citation | Huang, X.,Zheng, Y.,Zhang, F.,Wei, Z.,Wang, Y.,Carrell, R.W.,Read, R.J.,Chen, G.Q.,Zhou, A. Molecular Mechanism of Z alpha 1-Antitrypsin Deficiency J. Biol. Chem., 291:15674-15686, 2016 Cited by PubMed Abstract: The Z mutation (E342K) of α1-antitrypsin (α1-AT), carried by 4% of Northern Europeans, predisposes to early onset of emphysema due to decreased functional α1-AT in the lung and to liver cirrhosis due to accumulation of polymers in hepatocytes. However, it remains unclear why the Z mutation causes intracellular polymerization of nascent Z α1-AT and why 15% of the expressed Z α1-AT is secreted into circulation as functional, but polymerogenic, monomers. Here, we solve the crystal structure of the Z-monomer and have engineered replacements to assess the conformational role of residue Glu-342 in α1-AT. The results reveal that Z α1-AT has a labile strand 5 of the central β-sheet A (s5A) with a consequent equilibrium between a native inhibitory conformation, as in its crystal structure here, and an aberrant conformation with s5A only partially incorporated into the central β-sheet. This aberrant conformation, induced by the loss of interactions from the Glu-342 side chain, explains why Z α1-AT is prone to polymerization and readily binds to a 6-mer peptide, and it supports that annealing of s5A into the central β-sheet is a crucial step in the serpins' metastable conformational formation. The demonstration that the aberrant conformation can be rectified through stabilization of the labile s5A by binding of a small molecule opens a potential therapeutic approach for Z α1-AT deficiency. PubMed: 27246852DOI: 10.1074/jbc.M116.727826 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.34 Å) |
Structure validation
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