4wxv

From Proteopedia

(Difference between revisions)

Revision as of 08:41, 4 December 2019

Human cationic trypsin K97D mutant in complex with bovine pancreatic trypsin inhibitor (BPTI)

Structural highlights

4wxv is a 4 chain structure with sequence from Bovin and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	4wwy
Gene:	PRSS1, TRP1, TRY1, TRYP1 (HUMAN)
Activity:	Trypsin, with EC number 3.4.21.4
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.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11]

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.^[12] [BPT1_BOVIN] Inhibits trypsin, kallikrein, chymotrypsin, and plasmin.

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^[13]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Teich N, Ockenga J, Hoffmeister A, Manns M, Mossner J, Keim V. Chronic pancreatitis associated with an activation peptide mutation that facilitates trypsin activation. Gastroenterology. 2000 Aug;119(2):461-5. PMID:10930381
↑ Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, Martin SP, Gates LK Jr, Amann ST, Toskes PP, Liddle R, McGrath K, Uomo G, Post JC, Ehrlich GD. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet. 1996 Oct;14(2):141-5. PMID:8841182 doi:10.1038/ng1096-141
↑ Teich N, Bauer N, Mossner J, Keim V. Mutational screening of patients with nonalcoholic chronic pancreatitis: identification of further trypsinogen variants. Am J Gastroenterol. 2002 Feb;97(2):341-6. PMID:11866271 doi:10.1111/j.1572-0241.2002.05467.x
↑ Gorry MC, Gabbaizedeh D, Furey W, Gates LK Jr, Preston RA, Aston CE, Zhang Y, Ulrich C, Ehrlich GD, Whitcomb DC. Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis. Gastroenterology. 1997 Oct;113(4):1063-8. PMID:9322498
↑ Teich N, Mossner J, Keim V. Mutations of the cationic trypsinogen in hereditary pancreatitis. Hum Mutat. 1998;12(1):39-43. PMID:9633818 doi:<39::AID-HUMU6>3.0.CO;2-P 10.1002/(SICI)1098-1004(1998)12:1<39::AID-HUMU6>3.0.CO;2-P
↑ Witt H, Luck W, Becker M. A signal peptide cleavage site mutation in the cationic trypsinogen gene is strongly associated with chronic pancreatitis. Gastroenterology. 1999 Jul;117(1):7-10. PMID:10381903
↑ Ferec C, Raguenes O, Salomon R, Roche C, Bernard JP, Guillot M, Quere I, Faure C, Mercier B, Audrezet MP, Guillausseau PJ, Dupont C, Munnich A, Bignon JD, Le Bodic L. Mutations in the cationic trypsinogen gene and evidence for genetic heterogeneity in hereditary pancreatitis. J Med Genet. 1999 Mar;36(3):228-32. PMID:10204851
↑ Chen JM, Raguenes O, Ferec C, Deprez PH, Verellen-Dumoulin C. A CGC>CAT gene conversion-like event resulting in the R122H mutation in the cationic trypsinogen gene and its implication in the genotyping of pancreatitis. J Med Genet. 2000 Nov;37(11):E36. PMID:11073545
↑ Pfutzer R, Myers E, Applebaum-Shapiro S, Finch R, Ellis I, Neoptolemos J, Kant JA, Whitcomb DC. Novel cationic trypsinogen (PRSS1) N29T and R122C mutations cause autosomal dominant hereditary pancreatitis. Gut. 2002 Feb;50(2):271-2. PMID:11788572
↑ Teich N, Le Marechal C, Kukor Z, Caca K, Witzigmann H, Chen JM, Toth M, Mossner J, Keim V, Ferec C, Sahin-Toth M. Interaction between trypsinogen isoforms in genetically determined pancreatitis: mutation E79K in cationic trypsin (PRSS1) causes increased transactivation of anionic trypsinogen (PRSS2). Hum Mutat. 2004 Jan;23(1):22-31. PMID:14695529 doi:10.1002/humu.10285
↑ Teich N, Nemoda Z, Kohler H, Heinritz W, Mossner J, Keim V, Sahin-Toth M. Gene conversion between functional trypsinogen genes PRSS1 and PRSS2 associated with chronic pancreatitis in a six-year-old girl. Hum Mutat. 2005 Apr;25(4):343-7. PMID:15776435 doi:10.1002/humu.20148
↑ Koshikawa N, Yasumitsu H, Nagashima Y, Umeda M, Miyazaki K. Identification of one- and two-chain forms of trypsinogen 1 produced by a human gastric adenocarcinoma cell line. Biochem J. 1994 Oct 1;303 ( Pt 1):187-90. PMID:7945238
↑ Alloy AP, Kayode O, Wang R, Hockla A, Soares AS, Radisky ES. Mesotrypsin Has Evolved Four Unique Residues to Cleave Trypsin Inhibitors as Substrates. J Biol Chem. 2015 Jul 14. pii: jbc.M115.662429. PMID:26175157 doi:http://dx.doi.org/10.1074/jbc.M115.662429

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4wxv"

@@ Line 3: / Line 3: @@
 <StructureSection load='4wxv' size='340' side='right'caption='[[4wxv]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4wxv]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WXV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4WXV FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4wxv]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Bovin Bovin] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WXV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4WXV FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4wwy|4wwy]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PRSS1, TRP1, TRY1, TRYP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Trypsin Trypsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.4 3.4.21.4] </span></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4wxv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wxv OCA], [http://pdbe.org/4wxv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4wxv RCSB], [http://www.ebi.ac.uk/pdbsum/4wxv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4wxv ProSAT]</span></td></tr>
@@ Line 31: / Line 32: @@
 __TOC__
 </StructureSection>
+[[Category: Bovin]]
+[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: Trypsin]]

4wxv

From Proteopedia

Revision as of 08:41, 4 December 2019

Human cationic trypsin K97D mutant in complex with bovine pancreatic trypsin inhibitor (BPTI)

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox