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


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. Study holds ProTherm entries: 11578, 11579, 11580, 11581, 11582, 11583, 11584, 11585, 11586, 11587, 11588, 11589, 11590, 11591, 11592, 11593, 11594, 11595, 11596, 11597, 11598, 11599, 11600, 11601, 11602, 11603, 11604, 11605 Extra Details: additive : EDTA(1 mM), alpha1-antitrypsin; cavity-filling mutations; conformational stability;,native strain; molecular packing

Submission Details


Submitter: Connie Wang

Submission Date: April 24, 2018, 8:42 p.m.

Version: 1

Publication Details
Lee C;Maeng JS;Kocher JP;Lee B;Yu MH,Protein Sci. (2001) Cavities of alpha(1)-antitrypsin that play structural and functional roles. PMID:11420446
Additional Information

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
100.0 Alpha-1-antitrypsin P01009 A1AT_HUMAN
96.4 Alpha-1-antitrypsin Q5RCW5 A1AT_PONAB
92.4 Alpha-1-antitrypsin P01010 A1AT_PAPAN
93.1 Alpha-1-antitrypsin O00394 A1AT_CHLAE