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. 1998 Feb;7(2):283–292. doi: 10.1002/pro.5560070207

Structures of adamalysin II with peptidic inhibitors. Implications for the design of tumor necrosis factor alpha convertase inhibitors.

F X Gomis-Rüth 1, E F Meyer 1, L F Kress 1, V Politi 1
PMCID: PMC2143928  PMID: 9521103

Abstract

Crotalus adamanteus snake venom adamalysin II is the structural prototype of the adamalysin or ADAM family comprising proteolytic domains of snake venom metalloproteinases, multimodular mammalian reproductive tract proteins, and tumor necrosis factor alpha convertase, TACE, involved in the release of the inflammatory cytokine, TNFalpha. The structure of adamalysin II in noncovalent complex with two small-molecule right-hand side peptidomimetic inhibitors (Pol 647 and Pol 656) has been solved using X-ray diffraction data up to 2.6 and 2.8 A resolution. The inhibitors bind to the S'-side of the proteinase, inserting between two protein segments, establishing a mixed parallel-antiparallel three-stranded beta-sheet and coordinate the central zinc ion in a bidentate manner via their two C-terminal oxygen atoms. The proteinase-inhibitor complexes are described in detail and are compared with other known structures. An adamalysin-based model of the active site of TACE reveals that these small molecules would probably fit into the active site cleft of this latter metalloproteinase, providing a starting model for the rational design of TACE inhibitors.

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Selected References

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  1. Alfandari D., Wolfsberg T. G., White J. M., DeSimone D. W. ADAM 13: a novel ADAM expressed in somitic mesoderm and neural crest cells during Xenopus laevis development. Dev Biol. 1997 Feb 15;182(2):314–330. doi: 10.1006/dbio.1996.8458. [DOI] [PubMed] [Google Scholar]
  2. Bjarnason J. B., Fox J. W. Hemorrhagic metalloproteinases from snake venoms. Pharmacol Ther. 1994;62(3):325–372. doi: 10.1016/0163-7258(94)90049-3. [DOI] [PubMed] [Google Scholar]
  3. Black R. A., Rauch C. T., Kozlosky C. J., Peschon J. J., Slack J. L., Wolfson M. F., Castner B. J., Stocking K. L., Reddy P., Srinivasan S. A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature. 1997 Feb 20;385(6618):729–733. doi: 10.1038/385729a0. [DOI] [PubMed] [Google Scholar]
  4. Bode W., Gomis-Rüth F. X., Stöckler W. Astacins, serralysins, snake venom and matrix metalloproteinases exhibit identical zinc-binding environments (HEXXHXXGXXH and Met-turn) and topologies and should be grouped into a common family, the 'metzincins'. FEBS Lett. 1993 Sep 27;331(1-2):134–140. doi: 10.1016/0014-5793(93)80312-i. [DOI] [PubMed] [Google Scholar]
  5. Bode W., Reinemer P., Huber R., Kleine T., Schnierer S., Tschesche H. The X-ray crystal structure of the catalytic domain of human neutrophil collagenase inhibited by a substrate analogue reveals the essentials for catalysis and specificity. EMBO J. 1994 Mar 15;13(6):1263–1269. doi: 10.1002/j.1460-2075.1994.tb06378.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Botos I., Scapozza L., Zhang D., Liotta L. A., Meyer E. F. Batimastat, a potent matrix mealloproteinase inhibitor, exhibits an unexpected mode of binding. Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):2749–2754. doi: 10.1073/pnas.93.7.2749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Catanese J. J., Kress L. F. Isolation from opossum serum of a metalloproteinase inhibitor homologous to human alpha 1B-glycoprotein. Biochemistry. 1992 Jan 21;31(2):410–418. doi: 10.1021/bi00117a015. [DOI] [PubMed] [Google Scholar]
  8. Cheung H. S., Cushman D. W. Inhibition of homogeneous angiotensin-converting enzyme of rabbit lung by synthetic venom peptides of Bothrops jararaca. Biochim Biophys Acta. 1973 Feb 15;293(2):451–463. doi: 10.1016/0005-2744(73)90352-5. [DOI] [PubMed] [Google Scholar]
  9. Emi M., Katagiri T., Harada Y., Saito H., Inazawa J., Ito I., Kasumi F., Nakamura Y. A novel metalloprotease/disintegrin-like gene at 17q21.3 is somatically rearranged in two primary breast cancers. Nat Genet. 1993 Oct;5(2):151–157. doi: 10.1038/ng1093-151. [DOI] [PubMed] [Google Scholar]
  10. Gilardini Montani M. S., Tuosto L., Delfini M., Guerritore D., Starace G., Politi E., Piccolella E. A new tripeptide, Pol 509, influences biochemical events associated with antigen presentation efficiency of PPD-specific EBV-B cells. Immunopharmacology. 1993 Jan-Feb;25(1):51–63. doi: 10.1016/0162-3109(93)90030-t. [DOI] [PubMed] [Google Scholar]
  11. Gomis-Rüth F. X., Kress L. F., Bode W. First structure of a snake venom metalloproteinase: a prototype for matrix metalloproteinases/collagenases. EMBO J. 1993 Nov;12(11):4151–4157. doi: 10.1002/j.1460-2075.1993.tb06099.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Grams F., Dive V., Yiotakis A., Yiallouros I., Vassiliou S., Zwilling R., Bode W., Stöcker W. Structure of astacin with a transition-state analogue inhibitor. Nat Struct Biol. 1996 Aug;3(8):671–675. doi: 10.1038/nsb0896-671. [DOI] [PubMed] [Google Scholar]
  13. Grams F., Huber R., Kress L. F., Moroder L., Bode W. Activation of snake venom metalloproteinases by a cysteine switch-like mechanism. FEBS Lett. 1993 Nov 29;335(1):76–80. doi: 10.1016/0014-5793(93)80443-x. [DOI] [PubMed] [Google Scholar]
  14. Grams F., Reinemer P., Powers J. C., Kleine T., Pieper M., Tschesche H., Huber R., Bode W. X-ray structures of human neutrophil collagenase complexed with peptide hydroxamate and peptide thiol inhibitors. Implications for substrate binding and rational drug design. Eur J Biochem. 1995 Mar 15;228(3):830–841. doi: 10.1111/j.1432-1033.1995.tb20329.x. [DOI] [PubMed] [Google Scholar]
  15. Hite L. A., Fox J. W., Bjarnason J. B. A new family of proteinases is defined by several snake venom metalloproteinases. Biol Chem Hoppe Seyler. 1992 Jul;373(7):381–385. doi: 10.1515/bchm3.1992.373.2.381. [DOI] [PubMed] [Google Scholar]
  16. Hite L. A., Jia L. G., Bjarnason J. B., Fox J. W. cDNA sequences for four snake venom metalloproteinases: structure, classification, and their relationship to mammalian reproductive proteins. Arch Biochem Biophys. 1994 Jan;308(1):182–191. doi: 10.1006/abbi.1994.1026. [DOI] [PubMed] [Google Scholar]
  17. Huovila A. P., Almeida E. A., White J. M. ADAMs and cell fusion. Curr Opin Cell Biol. 1996 Oct;8(5):692–699. doi: 10.1016/s0955-0674(96)80111-6. [DOI] [PubMed] [Google Scholar]
  18. Kester W. R., Matthews B. W. Crystallographic study of the binding of dipeptide inhibitors to thermolysin: implications for the mechanism of catalysis. Biochemistry. 1977 May 31;16(11):2506–2516. doi: 10.1021/bi00630a030. [DOI] [PubMed] [Google Scholar]
  19. Kini R. M., Evans H. J. Structural domains in venom proteins: evidence that metalloproteinases and nonenzymatic platelet aggregation inhibitors (disintegrins) from snake venoms are derived by proteolysis from a common precursor. Toxicon. 1992 Mar;30(3):265–293. doi: 10.1016/0041-0101(92)90869-7. [DOI] [PubMed] [Google Scholar]
  20. Kress L. F., Catanese J. J. Identification of the cleavage sites resulting from enzymatic inactivation of human antithrombin III by Crotalus adamanteus proteinase II in the the presence and absence of heparin. Biochemistry. 1981 Dec 22;20(26):7432–7438. doi: 10.1021/bi00529a017. [DOI] [PubMed] [Google Scholar]
  21. Kurecki T., Laskowski M., Sr, Kress L. F. Purification and some properties of two proteinases from Crotalus adamanteus venom that inactivate human alpha 1-proteinase inhibitor. J Biol Chem. 1978 Nov 25;253(22):8340–8345. [PubMed] [Google Scholar]
  22. Kurisu G., Kinoshita T., Sugimoto A., Nagara A., Kai Y., Kasai N., Harada S. Structure of the zinc endoprotease from Streptomyces caespitosus. J Biochem. 1997 Feb;121(2):304–308. doi: 10.1093/oxfordjournals.jbchem.a021587. [DOI] [PubMed] [Google Scholar]
  23. Lunn C. A., Fan X., Dalie B., Miller K., Zavodny P. J., Narula S. K., Lundell D. Purification of ADAM 10 from bovine spleen as a TNFalpha convertase. FEBS Lett. 1997 Jan 6;400(3):333–335. doi: 10.1016/s0014-5793(96)01410-x. [DOI] [PubMed] [Google Scholar]
  24. McGeehan G. M., Becherer J. D., Bast R. C., Jr, Boyer C. M., Champion B., Connolly K. M., Conway J. G., Furdon P., Karp S., Kidao S. Regulation of tumour necrosis factor-alpha processing by a metalloproteinase inhibitor. Nature. 1994 Aug 18;370(6490):558–561. doi: 10.1038/370558a0. [DOI] [PubMed] [Google Scholar]
  25. Mohler K. M., Sleath P. R., Fitzner J. N., Cerretti D. P., Alderson M., Kerwar S. S., Torrance D. S., Otten-Evans C., Greenstreet T., Weerawarna K. Protection against a lethal dose of endotoxin by an inhibitor of tumour necrosis factor processing. Nature. 1994 Jul 21;370(6486):218–220. doi: 10.1038/370218a0. [DOI] [PubMed] [Google Scholar]
  26. Moss M. L., Jin S. L., Milla M. E., Bickett D. M., Burkhart W., Carter H. L., Chen W. J., Clay W. C., Didsbury J. R., Hassler D. Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature. 1997 Feb 20;385(6618):733–736. doi: 10.1038/385733a0. [DOI] [PubMed] [Google Scholar]
  27. Moura-da-Silva A. M., Laing G. D., Paine M. J., Dennison J. M., Politi V., Crampton J. M., Theakston R. D. Processing of pro-tumor necrosis factor-alpha by venom metalloproteinases: a hypothesis explaining local tissue damage following snake bite. Eur J Immunol. 1996 Sep;26(9):2000–2005. doi: 10.1002/eji.1830260905. [DOI] [PubMed] [Google Scholar]
  28. Neeper M. P., Jacobson M. A. Sequence of a cDNA encoding the platelet aggregation inhibitor trigramin. Nucleic Acids Res. 1990 Jul 25;18(14):4255–4255. doi: 10.1093/nar/18.14.4255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Nomura K., Suzuki N. Stereo-specific inhibition of sea urchin envelysin (hatching enzyme) by a synthetic autoinhibitor peptide with a cysteine-switch consensus sequence. FEBS Lett. 1993 Apr 19;321(1):84–88. doi: 10.1016/0014-5793(93)80626-6. [DOI] [PubMed] [Google Scholar]
  30. Robeva A., Politi V., Shannon J. D., Bjarnason J. B., Fox J. W. Synthetic and endogenous inhibitors of snake venom metalloproteinases. Biomed Biochim Acta. 1991;50(4-6):769–773. [PubMed] [Google Scholar]
  31. Rosenberg G. A., Estrada E. Y., Dencoff J. E., Stetler-Stevenson W. G. Tumor necrosis factor-alpha-induced gelatinase B causes delayed opening of the blood-brain barrier: an expanded therapeutic window. Brain Res. 1995 Dec 12;703(1-2):151–155. doi: 10.1016/0006-8993(95)01089-0. [DOI] [PubMed] [Google Scholar]
  32. Schechter I., Berger A. On the size of the active site in proteases. I. Papain. Biochem Biophys Res Commun. 1967 Apr 20;27(2):157–162. doi: 10.1016/s0006-291x(67)80055-x. [DOI] [PubMed] [Google Scholar]
  33. Springman E. B., Angleton E. L., Birkedal-Hansen H., Van Wart H. E. Multiple modes of activation of latent human fibroblast collagenase: evidence for the role of a Cys73 active-site zinc complex in latency and a "cysteine switch" mechanism for activation. Proc Natl Acad Sci U S A. 1990 Jan;87(1):364–368. doi: 10.1073/pnas.87.1.364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Stöcker W., Grams F., Baumann U., Reinemer P., Gomis-Rüth F. X., McKay D. B., Bode W. The metzincins--topological and sequential relations between the astacins, adamalysins, serralysins, and matrixins (collagenases) define a superfamily of zinc-peptidases. Protein Sci. 1995 May;4(5):823–840. doi: 10.1002/pro.5560040502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Wolfsberg T. G., White J. M. ADAMs in fertilization and development. Dev Biol. 1996 Dec 15;180(2):389–401. doi: 10.1006/dbio.1996.0313. [DOI] [PubMed] [Google Scholar]
  36. Yamakawa Y., Omori-Satoh T. Primary structure of the antihemorrhagic factor in serum of the Japanese Habu: a snake venom metalloproteinase inhibitor with a double-headed cystatin domain. J Biochem. 1992 Nov;112(5):583–589. doi: 10.1093/oxfordjournals.jbchem.a123944. [DOI] [PubMed] [Google Scholar]
  37. Zhang D., Botos I., Gomis-Rüth F. X., Doll R., Blood C., Njoroge F. G., Fox J. W., Bode W., Meyer E. F. Structural interaction of natural and synthetic inhibitors with the venom metalloproteinase, atrolysin C (form d). Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8447–8451. doi: 10.1073/pnas.91.18.8447. [DOI] [PMC free article] [PubMed] [Google Scholar]

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