5IO1

CRYSTAL STRUCTURE OF RECOMBINANT HUMAN Z ALPHA-1-ANTITRYPSIN

5IO1 の概要

• エントリーDOI: 10.2210/pdb5io1/pdb
• 分子名称: Alpha-1-antitrypsin, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• 機能のキーワード: serpins, acute phase, alternative splicing, blood coagulation, disease mutation, glycoprotein, hydrolase, polymorphism, protease, protease inhibitor, secreted, serine protease inhibitor, hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 90462.75

構造登録者

Zhou, A. (登録日: 2016-03-08, 公開日: 2016-06-08, 最終更新日: 2024-10-30)

主引用文献

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

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: 27246852
DOI: 10.1074/jbc.M116.727826

実験手法

X-RAY DIFFRACTION (3.34 Å)