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Solution structure of marinostatin, a natural ester-linked protein protease inhibitor.

Kanaori K, Kamei K, Taniguchi M, Koyama T, Yasui T, Takano R, Imada C, Tajima K, Hara S
Biochemistry 44 2462-8 (2005)
Cited: 13 times
EuropePMC logo PMID: 15709758

Abstract

Marinostatin is a unique protein protease inhibitor containing two ester linkages. We have purified a 12-residue marinostatin [MST(1-12), (1)FATMRYPSDSDE(12)] and determined the residues involved in the formation of the ester linkages and the solution structure by (1)H NMR spectroscopy and restrained molecular dynamics calculation. The two ester linkages of MST(1-12) are formed between hydroxyl and carboxyl groups, Thr(3)-Asp(9) and Ser(8)-Asp(11), indicating that MST(1-12) has two cyclic regions which are fused at the residues of Ser(8) and Asp(9). A strong NOE cross-peak between Tyr(6) H(alpha) and Pro(7) H(alpha) was observed, indicating that the Pro(7) residue takes a cis-conformation. Well-converged structures and hydrogen-deuterium experiments of MST(1-12) showed that the backbone NH proton of the P1'residue, Arg(5), is hydrogen-bonded to the carbonyl oxygen of the ester linkage between Thr(3) and Asp(9). To reveal the significance of the ester linkages, a marinostatin analogue, MST-2SS ((1)FACMRYPCCSCE(12)) with two disulfide bridges of Cys(3)-Cys(9) and Cys(8)-Cys(11), was also synthesized. The inhibitory activity of MST-2SS was as strong as that of MST(1-12), and the Pro(7) residue of MST-2SS also takes a cis-conformation. However, the exchange rate of the Arg(5) NH proton of MST-2SS was about 100 times faster than that of MST(1-12), and the structure calculation of MST-2SS was not converged on account of the small number of NOEs, indicating that MST-2SS takes a more flexible structure. The hydrogen acceptability of the ester linkage formed by the P2 position residue, Thr(3), is crucial for suppressing the fluctuation of the reactive site and sustaining the inhibitory activity, which enables marinostatin to be one of the smallest protease inhibitors in nature.

Reviews - 1ixu mentioned but not cited (1)

  1. Prokaryote-derived protein inhibitors of peptidases: A sketchy occurrence and mostly unknown function. Kantyka T, Rawlings ND, Potempa J. Biochimie 92 1644-1656 (2010)


Reviews citing this publication (3)

  1. Ribosomally synthesized and post-translationally modified peptide natural products: overview and recommendations for a universal nomenclature. Arnison PG, Bibb MJ, Bierbaum G, Bowers AA, Bugni TS, Bulaj G, Camarero JA, Campopiano DJ, Challis GL, Clardy J, Cotter PD, Craik DJ, Dawson M, Dittmann E, Donadio S, Dorrestein PC, Entian KD, Fischbach MA, Garavelli JS, Göransson U, Gruber CW, Haft DH, Hemscheidt TK, Hertweck C, Hill C, Horswill AR, Jaspars M, Kelly WL, Klinman JP, Kuipers OP, Link AJ, Liu W, Marahiel MA, Mitchell DA, Moll GN, Moore BS, Müller R, Nair SK, Nes IF, Norris GE, Olivera BM, Onaka H, Patchett ML, Piel J, Reaney MJ, Rebuffat S, Ross RP, Sahl HG, Schmidt EW, Selsted ME, Severinov K, Shen B, Sivonen K, Smith L, Stein T, Süssmuth RD, Tagg JR, Tang GL, Truman AW, Vederas JC, Walsh CT, Walton JD, Wenzel SC, Willey JM, van der Donk WA. Nat Prod Rep 30 108-160 (2013)
  2. Microbial and fungal protease inhibitors--current and potential applications. Sabotič J, Kos J. Appl Microbiol Biotechnol 93 1351-1375 (2012)
  3. Mechanism of Action of Ribosomally Synthesized and Post-Translationally Modified Peptides. Ongpipattanakul C, Desormeaux EK, DiCaprio A, van der Donk WA, Mitchell DA, Nair SK. Chem Rev 122 14722-14814 (2022)

Articles citing this publication (9)

  1. Leader Peptide-Free In Vitro Reconstitution of Microviridin Biosynthesis Enables Design of Synthetic Protease-Targeted Libraries. Reyna-González E, Schmid B, Petras D, Süssmuth RD, Dittmann E. Angew Chem Int Ed Engl 55 9398-9401 (2016)
  2. Bioinformatics-Guided Expansion and Discovery of Graspetides. Ramesh S, Guo X, DiCaprio AJ, De Lio AM, Harris LA, Kille BL, Pogorelov TV, Mitchell DA. ACS Chem Biol 16 2787-2797 (2021)
  3. Relationship between temporary inhibition and structure of disulfide-linkage analogs of marinostatin, a natural ester-linked protein protease inhibitor. Taniguchi M, Kamei K, Kanaori K, Koyama T, Yasui T, Takano R, Harada S, Tajima K, Imada C, Hara S. J Pept Res 66 49-58 (2005)
  4. Structure-activity relationship of marinostatin, a serine protease inhibitor isolated from a marine organism. Taichi M, Yamazaki T, Kawahara K, Motooka D, Nakamura S, Harada S, Teshima T, Ohkubo T, Kobayashi Y, Nishiuchi Y. J Pept Sci 16 329-336 (2010)
  5. Phylogenomic analysis of the diversity of graspetides and proteins involved in their biosynthesis. Makarova KS, Blackburne B, Wolf YI, Nikolskaya A, Karamycheva S, Espinoza M, Barry CE, Bewley CA, Koonin EV. Biol Direct 17 7 (2022)
  6. Resisting degradation by human elastase: commonality of design features shared by 'canonical' plant and bacterial macrocyclic protease inhibitor scaffolds. Brauer AB, McBride JD, Kelly G, Matthews SJ, Leatherbarrow RJ. Bioorg Med Chem 15 4618-4628 (2007)
  7. Development of a novel peptide inhibitor of subtilisin BPN'. Ishida K, Shimizu M, Wakasugi A, Matsui Y, Nakamura A, Kojima S. FEBS Open Bio 12 2057-2064 (2022)
  8. Discovery, Function, and Engineering of Graspetides. Choi B, Link AJ. Trends Chem 5 620-633 (2023)
  9. Role of the backbone conformation at position 7 in the structure and activity of marinostatin, an ester-linked serine protease inhibitor. Taichi M, Yamazaki T, Nishiuchi Y. Chembiochem 13 1895-1898 (2012)


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