9VDI

Crystal structure of the recombinant A1-antitrypsin F51L/M351V/M358V triple mutant

Summary for 9VDI

• Entry DOI: 10.2210/pdb9vdi/pdb
• Descriptor: Alpha-1-antitrypsin (1 entity in total)
• Functional Keywords: a1-antitrypsin, recombination
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 83633.49

Authors

Wang, B.,Lan, T.J.,Lin, M.,Wang, Y.J.,Li, L.F.,Lin, X.L. (deposition date: 2025-06-08, release date: 2026-04-15)

Primary citation

Yang, D.,Wang, B.,Wang, X.,Zhu, W.,Lan, T.,Lin, M.,Wang, Y.,Wei, X.,Li, L.,Lin, X.
Development of a chemically modified recombinant alpha 1-antitrypsin mutant expressed in E. coli for therapeutic applications.
Int.J.Biol.Macromol., 339:149972-149972, 2026

PubMed Abstract: Alpha-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.

PubMed: 41475648
DOI: 10.1016/j.ijbiomac.2025.149972

Experimental method

X-RAY DIFFRACTION (2.6 Å)