Abstract
SLPI (secretory leukocyte protease inhibitor) is a 107-residue protease inhibitor which inhibits various serine proteases, including elastase, cathepsin G, chymotrypsin and trypsin. SLPI is obtained as a multiple inhibitor in lung defense and in chronic airway infection. X-ray crystal structures have so far reported that they are full-length SLPIs with bovine α-chymotrypsin and 1/2SLPI (recombinant C-terminal domain of SLPI; Arg58-Ala107) with HNE (human neutrophil elastase). To understand the role of this multiple inhibitory mechanism, the crystal structure of 1/2SLPI with porcine pancreas trypsin was solved and the binding modes of two other complexes compared. The Leu residue surprisingly interacts with the S1 site of trypsin, as with chymotrypsin and elastase. The inhibitory mechanism of 1/2SLPI using the wide primary binding site contacts (from P2' to P5) with various serine proteases is discussed. These inhibitory mechanisms have been acquired in the evolution of the protection system for acute inflammatory diseases.
Highlights
Secretory leukocyte protease inhibitor (SLPI) is a nonglycosylated serine protease inhibitor of 107 amino acids
The exact physiological function of SLPI has not been elucidated, but its major role is considered to be the protection of the airway epithelial surface from attached human neutrophil elastase which has been found in pulmonary lavage fluid and sputum from patients with inflammatory respiratory diseases (Scott et al, 2011; Zani et al, 2011)
The collected data were processed with CrystalClear version 1.3.5 and solved by the molecular replacement method using the CCP4 version 4.2 suite with the X-ray structure of 1/2SLPI [Protein Data Bank (PDB) code: 2z7f; Koizumi et al, 2008] and the structure of PPT (PDB code: 1avw; Song & Suh, 1998) as search models
Summary
Secretory leukocyte protease inhibitor (SLPI) is a nonglycosylated serine protease inhibitor of 107 amino acids. It inhibits various serine proteases, including elastase, cathepsin G, chymotrypsin and trypsin (Seemuller et al, 1986; Smith & Johnson, 1985; Thompson & Ohlsson, 1986). 1/2SLPI (recombinant C-terminal domain of SLPI Arg58–Ala107) has a potent inhibitory activity against multiple serine proteases such as trypsin, chymotrypsin, elastase, chymase and cathepsin G as that of intact SLPI (Korkmaz et al, 2010; Masuda et al, 1995; Rao et al, 1993). The present work describes the first X-ray structure analyses of 1/2SLPI with P1 Leu residue with trypsin (PPT) at 2.0 Aand comparisons are made with the previously reported 1/2SLPI–HNE and SLPI– chymotrypsin complex structures. We discuss the inhibitory mechanism of 1/2SLPI against various serine proteases
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