7qe8

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Human cationic trypsin (TRY1) complexed with serine protease inhibitor Kazal type 1 (SPINK1)

Structural highlights

7qe8 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.9Å
Ligands: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.[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]

Publication Abstract from PubMed

(1) The serine protease inhibitor Kazal type 1 (SPINK1) inhibits trypsin activity in zymogen granules of pancreatic acinar cells. Several mutations in the SPINK1 gene are associated with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). The most common variant is SPINK1 p.N34S. Although this mutation was identified two decades ago, the mechanism of action has remained elusive. (2) SPINK1 and human cationic trypsin (TRY1) were expressed in E. coli, and inhibitory activities were determined. Crystals of SPINK1-TRY1 complexes were grown by using the hanging-drop method, and phases were solved by molecular replacement. (3) Both SPINK1 variants show similar inhibitory behavior toward TRY1. The crystal structures are almost identical, with minor differences in the mutated loop. Both complexes show an unexpected rotamer conformation of the His63 residue in TRY1, which is a member of the catalytic triad. (4) The SPINK1 p.N34S mutation does not affect the inhibitory behavior or the overall structure of the protein. Therefore, the pathophysiological mechanism of action of the p.N34S variant cannot be explained mechanistically or structurally at the protein level. The observed histidine conformation is part of a mechanism for SPINK1 that can explain the exceptional proteolytic stability of this inhibitor.

Structural and Biophysical Insights into SPINK1 Bound to Human Cationic Trypsin.,Nagel F, Palm GJ, Geist N, McDonnell TCR, Susemihl A, Girbardt B, Mayerle J, Lerch MM, Lammers M, Delcea M Int J Mol Sci. 2022 Mar 23;23(7):3468. doi: 10.3390/ijms23073468. PMID:35408828[13]

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

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Citations
1 reviews cite this structure
Extracellular proteolysis in cancer: Proteases, substrates, and mechanisms in tumor progression and metastasis.
Radisky et al. (2024)
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See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ 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
  11. ↑ 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
  12. ↑ 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
  13. ↑ Nagel F, Palm GJ, Geist N, McDonnell TCR, Susemihl A, Girbardt B, Mayerle J, Lerch MM, Lammers M, Delcea M. Structural and Biophysical Insights into SPINK1 Bound to Human Cationic Trypsin. Int J Mol Sci. 2022 Mar 23;23(7):3468. PMID:35408828 doi:10.3390/ijms23073468

Contents


PDB ID 7qe8

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