1OPH

NON-COVALENT COMPLEX BETWEEN ALPHA-1-PI-PITTSBURGH AND S195A TRYPSIN

Summary for 1OPH

• Entry DOI: 10.2210/pdb1oph/pdb
• Related: 1EJM 1OO8 1QLP
• Descriptor: Alpha-1-antitrypsin precursor, Trypsinogen, cationic precursor (3 entities in total)
• Functional Keywords: serine proteinase inhibitor, michaelis-like complex, serpin, alpha-1 antitrypsin, trypsin, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted. Short peptide from AAT: Secreted, extracellular space, extracellular matrix: P01009; Secreted, extracellular space: P00760
• Total number of polymer chains: 2
• Total formula weight: 69704.98

Authors

Dementiev, A.,Simonovic, M.,Volz, K.,Gettins, P.G. (deposition date: 2003-03-05, release date: 2003-08-05, Last modification date: 2024-11-20)

Primary citation

Dementiev, A.,Simonovic, M.,Volz, K.,Gettins, P.G.
Canonical inhibitor-like interactions explain reactivity of alpha1-proteinase inhibitor Pittsburgh and antithrombin with proteinases
J.Biol.Chem., 278:37881-37887, 2003

PubMed Abstract: The serpin antithrombin is a slow thrombin inhibitor that requires heparin to enhance its reaction rate. In contrast, alpha1-proteinase inhibitor (alpha1PI) Pittsburgh (P1 Met --> Arg natural variant) inhibits thrombin 17 times faster than pentasaccharide heparin-activated antithrombin. We present here x-ray structures of free and S195A trypsin-bound alpha1PI Pittsburgh, which show that the reactive center loop (RCL) possesses a canonical conformation in the free serpin that does not change upon binding to S195A trypsin and that contacts the proteinase only between P2 and P2'. By inference from the structure of heparin cofactor II bound to S195A thrombin, this RCL conformation is also appropriate for binding to thrombin. Reaction rates of trypsin and thrombin with alpha1PI Pittsburgh and antithrombin and their P2 variants show that the low antithrombin-thrombin reaction rate results from the antithrombin RCL sequence at P2 and implies that, in solution, the antithrombin RCL must be in a similar canonical conformation to that found here for alpha1PI Pittsburgh, even in the nonheparin-activated state. This suggests a general, limited, canonical-like interaction between serpins and proteinases in their Michaelis complexes.

PubMed: 12860985
DOI: 10.1074/jbc.M305195200

Experimental method

X-RAY DIFFRACTION (2.3 Å)