Cavities of α1-antitrypsin that play structural and functional roles

Cheolju Lee, Jin Soo Maeng, Jean Pierre Kocher, Byungkook Lee, Myeong Hee Yu

Research output: Contribution to journalArticle

40 Scopus citations


The native form of inhibitory serine protease inhibitors (serpins) is strained, which is critical for their inhibitory activity. Previous studies on stabilizing mutations of α1-antitrypsin, a prototype of serpins, indicated that cavities provide a structural basis for the native strain of the molecule. We have systematically mapped the cavities of α1-antitrypsin that play such structural and functional roles by designing cavity-filling mutations at residues that line the walls of the cavities. Results show that energetically unfavorable cavities are distributed throughout the α1-antitrypsin molecule, and the cavity-filling mutations stabilized the native conformation at 8 out of 10 target sites. The stabilization effect of the individual cavity-filling mutations of α1-antitrypsin varied (0.2-1.9 kcal/mol for each additional methylene group) and appeared to depend largely on the structural flexibility of the cavity environment. Cavity-filling mutations that decreased inhibitory activity of α1-antitrypsin were localized in the loop regions that interact with β-sheet A distal from the reactive center loop. The results are consistent with the notion that β-sheet A and the structure around it mobilize when α1-antitrypsin forms a complex with a target protease.

Original languageEnglish (US)
Pages (from-to)1446-1453
Number of pages8
JournalProtein Science
Issue number7
StatePublished - 2001


  • Cavity-filling mutations
  • Conformational stability
  • Molecular packing
  • Native strain
  • α-antitrypsin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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