4wwy

human cationic trypsin G193R mutant in complex with bovine pancreatic trypsin inhibitor

spinqualitylabelsall models 4wwy, resolution 1.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4wwy is a 4 chain structure with sequence from Bos taurus and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.7Å Ligands: CA, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease TRY1_HUMAN Defects in PRSS1 are a cause of pancreatitis (PCTT) [MIM:167800. A disease characterized by the presence of calculi in pancreatic ducts. It causes severe abdominal pain attacks. Function TRY1_HUMAN Has activity against the synthetic substrates Boc-Phe-Ser-Arg-Mec, Boc-Leu-Thr-Arg-Mec, Boc-Gln-Ala-Arg-Mec and Boc-Val-Pro-Arg-Mec. The single-chain form is more active than the two-chain form against all of these substrates. Publication Abstract from PubMed Human mesotrypsin is highly homologous to other mammalian trypsins, and yet is functionally unique in possessing resistance to inhibition by canonical serine protease inhibitors and in cleaving these inhibitors as preferred substrates. Arg-193 and Ser-39 have been identified as contributors to the inhibitor resistance and cleavage capability of mesotrypsin, but it is not known whether these residues fully account for the unusual properties of mesotrypsin. Here we use human cationic trypsin as a template for engineering a gain of catalytic function, assessing mutants containing mesotrypsin-like mutations for resistance to inhibition by bovine pancreatic trypsin inhibitor (BPTI) and amyloid precursor protein Kunitz protease inhibitor (APPI), and for the ability to hydrolyze these inhibitors as substrates. We find that Arg-193 and Ser-39 are sufficient to confer mesotrypsin-like resistance to inhibition; however, compared with mesotrypsin, the trypsin-Y39S/G193R double mutant remains 10-fold slower at hydrolyzing BPTI and 2.5-fold slower at hydrolyzing APPI. We identify two additional residues in mesotrypsin, Lys-74 and Asp-97, which in concert with Arg-193 and Ser-39 confer the full catalytic capability of mesotrypsin for proteolysis of BPTI and APPI. Novel crystal structures of trypsin mutants in complex with BPTI suggest that these four residues function cooperatively to favor conformational dynamics that assist in dissociation of cleaved inhibitors. Our results reveal that efficient inhibitor cleavage is a complex capability to which at least four spatially separated residues of mesotrypsin contribute. These findings suggest that inhibitor cleavage represents a functional adaptation of mesotrypsin that may have evolved in response to positive selection pressure. Mesotrypsin Has Evolved Four Unique Residues to Cleave Trypsin Inhibitors as Substrates.,Alloy AP, Kayode O, Wang R, Hockla A, Soares AS, Radisky ES J Biol Chem. 2015 Jul 14. pii: jbc.M115.662429. PMID:26175157 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also BPTI 3D structures Trypsin 3D structures Trypsin inhibitor 3D structures

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