Crystal Structures of the complexes of C-terminal lobe of lactoferrin with NSAIDS : Structural basis of the prevention of NSAID induced gastropathy by lactoferrin revealed

Department of Biophysics, All India Institute of Medical Sciences
â—‹Mau Sinha Sujata Sharma Nagendra Singh Tej P Singh

Non steroidal anti-inflammatory drugs (NSAIDS) are the most commonly prescribed drugs for various inflammatory disorders. However, use of NSAIDs is accompanied by risk of upper and lower gastrointestinal (GI) complications, some of which can be serious or even fatal. Lactoferrin is an 80 kDa glycoprotein found in various biological fluids which consists of two homologous lobes each containing a single ferric ion. The C-terminal molecular half (C-lobe) of bovine lactoferrin was produced proteolytically. It consists of Tyr 342 to Ser 676 and Leu 681 to Phe 686. The structures of the complexes of C-lobe have been determined with three NSAIDS ; aspirin, indomethacin and diclofenac. These structures have revealed three additional zinc binding sites and a new site for the binding of NSAIDS. These results indicate new roles of lactoferrin C-lobe in regulating the roles of zinc ions and exhibits its potential of sequestering the NSAIDs in the human body. The structures of C-lobes also revealed a new role for the N-terminal residues of C-lobe which were involved in the interactions with N-lobe at the interface in the intact lactoferrin. The three potential glycosylation sites at Asn 368, Asn 476 and Asn 545 in the C-lobe are indeed glycosylated and contain 13 sugar residues. These structures reveal the mechanism by which lactoferrin is effective at preventing NSAID-induced intestinal injury.