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 journalArticlepeer-review

41 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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