Lee, C Maeng, JS Kocher, JP Lee, B Yu, MH 2024-01-21T12:09:10Z 2024-01-21T12:09:10Z 2021-09-05 2001-07 0961-8368 https://pubs.kist.re.kr/handle/201004/140364 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. English COLD SPRING HARBOR LAB PRESS REACTIVE CENTER LOOP AMINO-ACID SUBSTITUTIONS PROTEIN STRUCTURES INFLUENZA HEMAGGLUTININ INHIBITORY MECHANISM GLOBULAR-PROTEINS INTERNAL CAVITIES HYDROPHOBIC CORE BURIED WATERS PACKING Cavities of alpha(1)-antitrypsin that play structural and functional roles Article 10.1110/ps.840101 1 PROTEIN SCIENCE, v.10, no.7, pp.1446 - 1453 PROTEIN SCIENCE 10 7 1446 1453 scie scopus 000169457200017 2-s2.0-0034976979 Biochemistry & Molecular Biology Biochemistry & Molecular Biology Article REACTIVE CENTER LOOP AMINO-ACID SUBSTITUTIONS PROTEIN STRUCTURES INFLUENZA HEMAGGLUTININ INHIBITORY MECHANISM GLOBULAR-PROTEINS INTERNAL CAVITIES HYDROPHOBIC CORE BURIED WATERS PACKING alpha(1)-antitrypsin cavity-filling mutations conformational stability native strain molecular packing