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Protein Sci. 2001 Jul;10(7):1446-53.

Cavities of alpha(1)-antitrypsin that play structural and functional roles.

Author information

1
National Creative Research Initiatives, Protein Strain Research Center, Korea Institute of Science and Technology, Cheongryang, Seoul 130-650, Korea.

Abstract

The native form of inhibitory serine protease inhibitors (serpins) is strained, which is critical for their inhibitory activity. Previous studies on stabilizing mutations of alpha(1)-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 alpha(1)-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 alpha(1)-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 alpha(1)-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 alpha(1)-antitrypsin were localized in the loop regions that interact with beta-sheet A distal from the reactive center loop. The results are consistent with the notion that beta-sheet A and the structure around it mobilize when alpha(1)-antitrypsin forms a complex with a target protease.

PMID:
11420446
PMCID:
PMC2374102
DOI:
10.1110/ps.840101
[Indexed for MEDLINE]
Free PMC Article

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