4HGC

Crystal structure of bovine trypsin complexed with sfti-1 analog containing a peptoid residue at position p1

Summary for 4HGC

• Entry DOI: 10.2210/pdb4hgc/pdb
• Related: 1SFI 3MI4 3P8F
• Related PRD ID: PRD_001025
• Descriptor: Cationic trypsin, Trypsin inhibitor 1, CALCIUM ION, ... (6 entities in total)
• Functional Keywords: hydrolase, serine protease, cyclic peptide, peptoid, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Bos taurus (cow); More
• Cellular location: Secreted, extracellular space: P00760
• Total number of polymer chains: 2
• Total formula weight: 25647.85

Authors

Krzywda, S.,Jaskolski, M.,Rolka, K.,Stawikowski, M. (deposition date: 2012-10-08, release date: 2013-10-09, Last modification date: 2023-11-15)

Primary citation

Krzywda, S.,Jaskolski, M.,Rolka, K.,Stawikowski, M.J.
Structure of a proteolytically resistant analogue of (NLys)(5)SFTI-1 in complex with trypsin: evidence for the direct participation of the Ser214 carbonyl group in serine protease-mediated proteolysis.
Acta Crystallogr.,Sect.D, 70:668-675, 2014

PubMed Abstract: Peptide-peptoid hybrids are found to be potent inhibitors of serine proteases. These engineered peptidomimetics benefit from both types of units of the biopolymeric structure: the natural inhibitor part serves as a good binding template, while the P1-positioned peptoid component provides complete resistance towards proteolysis. In this report, the mechanism of proteolytic resistance of a P1 peptoid-containing analogue is postulated based on the crystal structure of the (NLys)(5)-modified sunflower trypsin inhibitor SFTI-1 in complex with bovine trypsin solved at 1.29 Å resolution. The structural differences between the (NLys)(5)SFTI-1-trypsin complex and the native SFTI-1-trypsin complex are surprisingly small and reveal the key role of the carbonyl group of the Ser214 residue of the enzyme, which is crucial for binding of the inhibitor and plays a crucial role in proteolysis mediated by serine proteases. The incorporated NLys5 peptoid residue prevents Ser214 from forming a hydrogen bond to the P1 residue, and in turn Gln192 does not form a hydrogen bond to the carbonyl group of the P2 residue. It also increases the distance between the Ser214 carbonyl group and the Ser195 residue, thus preventing proteolysis. The hybrid inhibitor structure reported here provides insight into protein-protein interaction, which can be efficiently and selectively probed with the use of peptoids incorporated within endogenous peptide ligands.

PubMed: 24598736
DOI: 10.1107/S1399004713032252

Experimental method

X-RAY DIFFRACTION (1.29 Å)