9vdi
Crystal structure of the recombinant A1-antitrypsin F51L/M351V/M358V triple mutant
Structural highlights
DiseaseA1AT_HUMAN Defects in SERPINA1 are the cause of alpha-1-antitrypsin deficiency (A1ATD) [MIM:613490. A disorder whose most common manifestation is emphysema, which becomes evident by the third to fourth decade. A less common manifestation of the deficiency is liver disease, which occurs in children and adults, and may result in cirrhosis and liver failure. Environmental factors, particularly cigarette smoking, greatly increase the risk of emphysema at an earlier age.[1] [2] [3] FunctionA1AT_HUMAN Inhibitor of serine proteases. Its primary target is elastase, but it also has a moderate affinity for plasmin and thrombin. Irreversibly inhibits trypsin, chymotrypsin and plasminogen activator. The aberrant form inhibits insulin-induced NO synthesis in platelets, decreases coagulation time and has proteolytic activity against insulin and plasmin.[:][4] [5] Short peptide from AAT: reversible chymotrypsin inhibitor. It also inhibits elastase, but not trypsin. Its major physiological function is the protection of the lower respiratory tract against proteolytic destruction by human leukocyte elastase (HLE).[:][6] [7] Publication Abstract from PubMedAlpha-1-antitrypsin (AAT) is an antiprotease that fulfills a critical physiological function in protecting the lungs from inflammation-induced damage. Inherited AAT deficiency (AATD) represents a clinically significant but often undiagnosed genetic disorder. Native AAT derived from human serum has been utilized as an effective therapeutic agent for treating hereditary emphysema due to AAT deficiency. However, its limited availability highlights the urgent need for recombinant alternatives. In this study, we successfully expressed a recombinant stable form of triple mutant AAT (TM-rAAT) in E. coli as inclusion bodies, which were subsequently refolded and purified to yield fully active TM-rAAT. The high-resolution crystal structure of TM-rAAT reveals that the mutations have minimal impact on the overall structure. To further enhance its therapeutic potential by extending the serum half-life, a chemical modification was introduced to rAAT. Kinetic studies in conjunction with animal experiments demonstrate that the chemically modified TM-rAAT retains full activity while exhibiting a significantly prolonged in vivo serum half-life. Collectively, our findings provide robust and compelling evidence supporting the efficiency of the procedures employed in the production of chemically modified TM-rAAT, demonstrating its strong potential for therapeutic development. Development of a chemically modified recombinant alpha1-antitrypsin mutant expressed in E. coli for therapeutic applications.,Yang D, Wang B, Wang X, Zhu W, Lan T, Lin M, Wang Y, Wei X, Li L, Lin X Int J Biol Macromol. 2026 Jan;339(Pt 1):149972. doi: , 10.1016/j.ijbiomac.2025.149972. Epub 2025 Dec 29. PMID:41475648[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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