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| | ==Human cationic trypsin complexed with bovine pancreatic trypsin inhibitor (BPTI)== | | ==Human cationic trypsin complexed with bovine pancreatic trypsin inhibitor (BPTI)== |
| - | <StructureSection load='2ra3' size='340' side='right' caption='[[2ra3]], [[Resolution|resolution]] 1.46Å' scene=''> | + | <StructureSection load='2ra3' size='340' side='right'caption='[[2ra3]], [[Resolution|resolution]] 1.46Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2ra3]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] and [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2RA3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2RA3 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2ra3]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2RA3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2RA3 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> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.46Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2r9p|2r9p]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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 Homo sapiens])</td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2ra3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ra3 OCA], [https://pdbe.org/2ra3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ra3 RCSB], [https://www.ebi.ac.uk/pdbsum/2ra3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ra3 ProSAT]</span></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>
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| - | <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=2ra3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ra3 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2ra3 RCSB], [http://www.ebi.ac.uk/pdbsum/2ra3 PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/TRY1_HUMAN TRY1_HUMAN]] Defects in PRSS1 are a cause of pancreatitis (PCTT) [MIM:[http://omim.org/entry/167800 167800]]. A disease characterized by the presence of calculi in pancreatic ducts. It causes severe abdominal pain attacks.<ref>PMID:10930381</ref> <ref>PMID:8841182</ref> <ref>PMID:11866271</ref> <ref>PMID:9322498</ref> <ref>PMID:9633818</ref> <ref>PMID:10381903</ref> <ref>PMID:10204851</ref> <ref>PMID:11073545</ref> <ref>PMID:11788572</ref> <ref>PMID:14695529</ref> <ref>PMID:15776435</ref> | + | [https://www.uniprot.org/uniprot/TRY1_HUMAN TRY1_HUMAN] Defects in PRSS1 are a cause of pancreatitis (PCTT) [MIM:[https://omim.org/entry/167800 167800]. A disease characterized by the presence of calculi in pancreatic ducts. It causes severe abdominal pain attacks.<ref>PMID:10930381</ref> <ref>PMID:8841182</ref> <ref>PMID:11866271</ref> <ref>PMID:9322498</ref> <ref>PMID:9633818</ref> <ref>PMID:10381903</ref> <ref>PMID:10204851</ref> <ref>PMID:11073545</ref> <ref>PMID:11788572</ref> <ref>PMID:14695529</ref> <ref>PMID:15776435</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/TRY1_HUMAN 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.<ref>PMID:7945238</ref> [[http://www.uniprot.org/uniprot/BPT1_BOVIN BPT1_BOVIN]] Inhibits trypsin, kallikrein, chymotrypsin, and plasmin. | + | [https://www.uniprot.org/uniprot/TRY1_HUMAN 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.<ref>PMID:7945238</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| | Check<jmol> | | Check<jmol> |
| | <jmolCheckbox> | | <jmolCheckbox> |
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ra/2ra3_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ra/2ra3_consurf.spt"</scriptWhenChecked> |
| - | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </jmolCheckbox> |
| - | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf]. | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2ra3 ConSurf]. |
| | <div style="clear:both"></div> | | <div style="clear:both"></div> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 2ra3" style="background-color:#fffaf0;"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Basic Pancreatic Trypsin Inhibitor|Basic Pancreatic Trypsin Inhibitor]] | + | *[[BPTI 3D structures|BPTI 3D structures]] |
| - | *[[Trypsin|Trypsin]] | + | *[[Trypsin 3D structures|Trypsin 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | [[Category: Bos taurus]] | | [[Category: Bos taurus]] |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Trypsin]] | + | [[Category: Large Structures]] |
| - | [[Category: Radisky, E S]] | + | [[Category: Radisky ES]] |
| - | [[Category: Salameh, M A]] | + | [[Category: Salameh MA]] |
| - | [[Category: Soares, A S]] | + | [[Category: Soares AS]] |
| - | [[Category: Bovine pancreatic trypsin inhibitor]]
| + | |
| - | [[Category: Bpti]]
| + | |
| - | [[Category: Digestion]]
| + | |
| - | [[Category: Disease mutation]]
| + | |
| - | [[Category: Human cationic trypsin]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Metal-binding]]
| + | |
| - | [[Category: Protease inhibitor]]
| + | |
| - | [[Category: Secreted]]
| + | |
| - | [[Category: Serine protease]]
| + | |
| - | [[Category: Serine protease inhibitor]]
| + | |
| - | [[Category: Sulfation]]
| + | |
| - | [[Category: Zymogen]]
| + | |
| Structural highlights
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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Human mesotrypsin is an isoform of trypsin that displays unusual resistance to polypeptide trypsin inhibitors and has been observed to cleave several such inhibitors as substrates. Whereas substitution of arginine for the highly conserved glycine 193 in the trypsin active site has been implicated as a critical factor in the inhibitor resistance of mesotrypsin, how this substitution leads to accelerated inhibitor cleavage is not clear. Bovine pancreatic trypsin inhibitor (BPTI) forms an extremely stable and cleavage-resistant complex with trypsin, and thus provides a rigorous challenge of mesotrypsin catalytic activity toward polypeptide inhibitors. Here, we report kinetic constants for mesotrypsin and the highly homologous (but inhibitor sensitive) human cationic trypsin, describing inhibition by, and cleavage of BPTI, as well as crystal structures of the mesotrypsin-BPTI and human cationic trypsin-BPTI complexes. We find that mesotrypsin cleaves BPTI with a rate constant accelerated 350-fold over that of human cationic trypsin and 150,000-fold over that of bovine trypsin. From the crystal structures, we see that small conformational adjustments limited to several side chains enable mesotrypsin-BPTI complex formation, surmounting the predicted steric clash introduced by Arg-193. Our results show that the mesotrypsin-BPTI interface favors catalysis through (a) electrostatic repulsion between the closely spaced mesotrypsin Arg-193 and BPTI Arg-17, and (b) elimination of two hydrogen bonds between the enzyme and the amine leaving group portion of BPTI. Our model predicts that these deleterious interactions accelerate leaving group dissociation and deacylation.
Structural basis for accelerated cleavage of bovine pancreatic trypsin inhibitor (BPTI) by human mesotrypsin.,Salameh MA, Soares AS, Hockla A, Radisky ES J Biol Chem. 2008 Feb 15;283(7):4115-23. Epub 2007 Dec 12. PMID:18077447[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Salameh MA, Soares AS, Hockla A, Radisky ES. Structural basis for accelerated cleavage of bovine pancreatic trypsin inhibitor (BPTI) by human mesotrypsin. J Biol Chem. 2008 Feb 15;283(7):4115-23. Epub 2007 Dec 12. PMID:18077447 doi:10.1074/jbc.M708268200
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