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The crystal structure of a major secreted aspartic proteinase from Candida albicans in complexes with two inhibitors.

Cutfield SM, Dodson EJ, Anderson BF, Moody PC, Marshall CJ, Sullivan PA, Cutfield JF
Structure 3 1261-71 (1995)
Cited: 57 times
EuropePMC logo PMID: 8591036

Abstract

Background

Infections caused by Candida albicans, a common fungal pathogen of humans, are increasing in incidence, necessitating development of new therapeutic drugs. Secreted aspartic proteinase (SAP) activity is considered an important virulence factor in these infections and might offer a suitable target for drug design. Amongst the various SAP isozymes, the SAP2 gene product is the major form expressed in a number of C. albicans strains.

Results

The three-dimensional structures of SAP2 complexed with the tight-binding inhibitor A70450 (a synthetic hexapeptide analogue) and with the general aspartic proteinase inhibitor pepstatin A (a microbial natural product) have been determined to 2.1 A and 3.0 A resolution, respectively. Although the protein structure retains the main features of a typical aspartic proteinase, it also shows some significant differences, due mainly to several sequence insertions and deletions (as revealed by homology modelling), that alter the shape of the binding cleft. There is also considerable variation in the C-terminal structural domain.

Conclusion

The differences in side chains, and in the conformations adopted by the two inhibitors, particularly at their P4, P3 and P'2 positions (using standard notation for protease-inhibitor residues), allows the A70450 structure to complement, more accurately, that of the substrate-binding site of SAP2. Some differences in the binding clefts of other SAP isoenzymes may be deduced from the SAP2 structure.

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  1. Candida albicans possesses Sap7 as a pepstatin A-insensitive secreted aspartic protease. Aoki W, Kitahara N, Miura N, Morisaka H, Yamamoto Y, Kuroda K, Ueda M. PLoS ONE 7 e32513 (2012)
  2. Antifungal effect of 4-arylthiosemicarbazides against Candida species. Search for molecular basis of antifungal activity of thiosemicarbazide derivatives. Siwek A, Stefańska J, Dzitko K, Ruszczak A. J Mol Model 18 4159-4170 (2012)
  3. Finding evolutionary relations beyond superfamilies: fold-based superfamilies. Matsuda K, Nishioka T, Kinoshita K, Kawabata T, Go N. Protein Sci 12 2239-2251 (2003)
  4. Repositioning Lopinavir, an HIV Protease Inhibitor, as a Promising Antifungal Drug: Lessons Learned from Candida albicans-In Silico, In Vitro and In Vivo Approaches. Santos ALS, Braga-Silva LA, Gonçalves DS, Ramos LS, Oliveira SSC, Souza LOP, Oliveira VS, Lins RD, Pinto MR, Muñoz JE, Taborda CP, Branquinha MH. J Fungi (Basel) 7 424 (2021)
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Reviews citing this publication (14)

  1. Candida albicans secreted aspartyl proteinases in virulence and pathogenesis. Naglik JR, Challacombe SJ, Hube B. Microbiol. Mol. Biol. Rev. 67 400-28, table of contents (2003)
  2. Cell wall and secreted proteins of Candida albicans: identification, function, and expression. Chaffin WL, López-Ribot JL, Casanova M, Gozalbo D, Martínez JP. Microbiol. Mol. Biol. Rev. 62 130-180 (1998)
  3. Molecular mechanisms for the conversion of zymogens to active proteolytic enzymes. Khan AR, James MN. Protein Sci. 7 815-836 (1998)
  4. Hydrolytic enzymes as virulence factors of Candida albicans. Schaller M, Borelli C, Korting HC, Hube B. Mycoses 48 365-377 (2005)
  5. Candida albicans proteinases and host/pathogen interactions. Naglik J, Albrecht A, Bader O, Hube B. Cell. Microbiol. 6 915-926 (2004)
  6. Metabolism impacts upon Candida immunogenicity and pathogenicity at multiple levels. Brown AJ, Brown GD, Netea MG, Gow NA. Trends Microbiol. 22 614-622 (2014)
  7. Aspartyl proteinases of Candida albicans and their role in pathogenicity. De Bernardis F, Sullivan PA, Cassone A. Med. Mycol. 39 303-313 (2001)
  8. Development of vaccines for Candida albicans: fighting a skilled transformer. Cassone A. Nat. Rev. Microbiol. 11 884-891 (2013)
  9. Current and future approaches to antimycotic treatment in the era of resistant fungi and immunocompromised hosts. Bastert J, Schaller M, Korting HC, Evans EG. Int. J. Antimicrob. Agents 17 81-91 (2001)
  10. Current state of three-dimensional characterisation of antifungal targets and its use for molecular modelling in drug design. Ruge E, Korting HC, Borelli C. Int. J. Antimicrob. Agents 26 427-441 (2005)
  11. Natural Antimicrobial Peptides as Inspiration for Design of a New Generation Antifungal Compounds. Bondaryk M, Staniszewska M, Zielińska P, Urbańczyk-Lipkowska Z. J Fungi (Basel) 3 (2017)
  12. The role of antibodies in protection against candidiasis. Matthews R, Burnie J. Res. Immunol. 149 343-52; discussion 496-9 (1998)
  13. Extracellular proteinases of Candida species pathogenic yeasts. Rapala-Kozik M, Bochenska O, Zajac D, Karkowska-Kuleta J, Gogol M, Zawrotniak M, Kozik A. Mol Oral Microbiol 33 113-124 (2018)
  14. From Naturally-Sourced Protease Inhibitors to New Treatments for Fungal Infections. Gutierrez-Gongora D, Geddes-McAlister J. J Fungi (Basel) 7 1016 (2021)

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  1. A triple deletion of the secreted aspartyl proteinase genes SAP4, SAP5, and SAP6 of Candida albicans causes attenuated virulence. Sanglard D, Hube B, Monod M, Odds FC, Gow NA. Infect. Immun. 65 3539-3546 (1997)
  2. KEX2 influences Candida albicans proteinase secretion and hyphal formation. Newport G, Agabian N. J. Biol. Chem. 272 28954-28961 (1997)
  3. Expression analysis of the Candida albicans lipase gene family during experimental infections and in patient samples. Stehr F, Felk A, Gácser A, Kretschmar M, Mähnss B, Neuber K, Hube B, Schäfer W. FEMS Yeast Res. 4 401-408 (2004)
  4. Proteolytic cleavage of covalently linked cell wall proteins by Candida albicans Sap9 and Sap10. Schild L, Heyken A, de Groot PW, Hiller E, Mock M, de Koster C, Horn U, Rupp S, Hube B. Eukaryotic Cell 10 98-109 (2011)
  5. Analysis of crystal structures of aspartic proteinases: on the role of amino acid residues adjacent to the catalytic site of pepsin-like enzymes. Andreeva NS, Rumsh LD. Protein Sci. 10 2439-2450 (2001)
  6. Structure of a secreted aspartic protease from C. albicans complexed with a potent inhibitor: implications for the design of antifungal agents. Abad-Zapatero C, Goldman R, Muchmore SW, Hutchins C, Stewart K, Navaza J, Payne CD, Ray TL. Protein Sci. 5 640-652 (1996)
  7. Human immunodeficiency virus type 1 protease inhibitor attenuates Candida albicans virulence properties in vitro. Gruber A, Speth C, Lukasser-Vogl E, Zangerle R, Borg-von Zepelin M, Dierich MP, Würzner R. Immunopharmacology 41 227-234 (1999)
  8. Enzymic characteristics of secreted aspartic proteases of Candida albicans. Koelsch G, Tang J, Loy JA, Monod M, Jackson K, Foundling SI, Lin X. Biochim. Biophys. Acta 1480 117-131 (2000)
  9. Barrel structures in proteins: automatic identification and classification including a sequence analysis of TIM barrels. Nagano N, Hutchinson EG, Thornton JM. Protein Sci. 8 2072-2084 (1999)
  10. Cloning and characterization of Sapp2p, the second aspartic proteinase isoenzyme from Candida parapsilosis. Merkerová M, Dostál J, Hradilek M, Pichová I, Hrusková-Heidingsfeldová O. FEMS Yeast Res 6 1018-1026 (2006)
  11. Activation mechanism, functional role and shedding of glycosylphosphatidylinositol-anchored Yps1p at the Saccharomyces cerevisiae cell surface. Gagnon-Arsenault I, Parisé L, Tremblay J, Bourbonnais Y. Mol. Microbiol. 69 982-993 (2008)
  12. Candida albicans secreted aspartic proteases 4-6 induce apoptosis of epithelial cells by a novel Trojan horse mechanism. Wu H, Downs D, Ghosh K, Ghosh AK, Staib P, Monod M, Tang J. FASEB J. 27 2132-2144 (2013)
  13. Structural characterization of activation 'intermediate 2' on the pathway to human gastricsin. Khan AR, Cherney MM, Tarasova NI, James MN. Nat. Struct. Biol. 4 1010-1015 (1997)
  14. The three-dimensional structure at 2.4 A resolution of glycosylated proteinase A from the lysosome-like vacuole of Saccharomyces cerevisiae. Aguilar CF, Cronin NB, Badasso M, Dreyer T, Newman MP, Cooper JB, Hoover DJ, Wood SP, Johnson MS, Blundell TL. J. Mol. Biol. 267 899-915 (1997)
  15. X-ray structures of Sap1 and Sap5: structural comparison of the secreted aspartic proteinases from Candida albicans. Borelli C, Ruge E, Lee JH, Schaller M, Vogelsang A, Monod M, Korting HC, Huber R, Maskos K. Proteins 72 1308-1319 (2008)
  16. HIV aspartyl protease inhibitors as promising compounds against Candida albicans André Luis Souza dos Santos. Dos Santos AL. World J Biol Chem 1 21-30 (2010)
  17. The crystal structure of the secreted aspartic proteinase 3 from Candida albicans and its complex with pepstatin A. Borelli C, Ruge E, Schaller M, Monod M, Korting HC, Huber R, Maskos K. Proteins 68 738-748 (2007)
  18. Insights into the selective inhibition of Candida albicans secreted aspartyl protease: a docking analysis study. Pranav Kumar SK, Kulkarni VM. Bioorg. Med. Chem. 10 1153-1170 (2002)
  19. The precursor of secreted aspartic proteinase Sapp1p from Candida parapsilosis can be activated both autocatalytically and by a membrane-bound processing proteinase. Dostál J, Dlouhá H, Malon P, Pichová I, Hrusková-Heidingsfeldová O. Biol. Chem. 386 791-799 (2005)
  20. Epitope mapping Candida albicans proteinase (SAP 2). Ghadjari A, Matthews RC, Burnie JP. FEMS Immunol. Med. Microbiol. 19 115-123 (1997)
  21. Inhibition of Candida albicans secreted aspartic protease by a novel series of peptidomimetics, also active on the HIV-1 protease. Skrbec D, Romeo D. Biochem. Biophys. Res. Commun. 297 1350-1353 (2002)
  22. The crystal structure of the secreted aspartic protease 1 from Candida parapsilosis in complex with pepstatin A. Dostál J, Brynda J, Hrusková-Heidingsfeldová O, Sieglová I, Pichová I, Rezácová P. J. Struct. Biol. 167 145-152 (2009)
  23. Design, synthesis, inhibition studies, and molecular modeling of pepstatin analogues addressing different secreted aspartic proteinases of Candida albicans. Cadicamo CD, Mortier J, Wolber G, Hell M, Heinrich IE, Michel D, Semlin L, Berger U, Korting HC, Höltje HD, Koksch B, Borelli C. Biochem. Pharmacol. 85 881-887 (2013)
  24. Experimental and computational active site mapping as a starting point to fragment-based lead discovery. Behnen J, Köster H, Neudert G, Craan T, Heine A, Klebe G. ChemMedChem 7 248-261 (2012)
  25. Triangular gold nanoparticles conjugated with peptide ligands: a new class of inhibitor for Candida albicans secreted aspartyl proteinase. Jebali A, Hajjar FH, Hekmatimoghaddam S, Kazemi B, De La Fuente JM, Rashidi M. Biochem. Pharmacol. 90 349-355 (2014)
  26. Homology modeling and SAR analysis of Schistosoma japonicum cathepsin D (SjCD) with statin inhibitors identify a unique active site steric barrier with potential for the design of specific inhibitors. Caffrey CR, Placha L, Barinka C, Hradilek M, Dostál J, Sajid M, McKerrow JH, Majer P, Konvalinka J, Vondrásek J. Biol. Chem. 386 339-349 (2005)
  27. Shift from persistent oral pseudomembranous to erythematous candidosis in a human immunodeficiency virus (HIV)-infected patient upon combination treatment with an HIV protease inhibitor. Hoegl L, Thoma-Greber E, Röcken M, Korting HC. Mycoses 41 213-217 (1998)
  28. Cis-Configured aziridines are new pseudo-irreversible dual-mode inhibitors of Candida albicans secreted aspartic protease 2. Degel B, Staib P, Rohrer S, Scheiber J, Martina E, Büchold C, Baumann K, Morschhäuser J, Schirmeister T. ChemMedChem 3 302-315 (2008)
  29. Penicillopepsin-JT2, a recombinant enzyme from Penicillium janthinellum and the contribution of a hydrogen bond in subsite S3 to k(cat). Cao QN, Stubbs M, Ngo KQ, Ward M, Cunningham A, Pai EF, Tu GC, Hofmann T. Protein Sci. 9 991-1001 (2000)
  30. Structure-based specificity mapping of secreted aspartic proteases of Candida parapsilosis, Candida albicans, and Candida tropicalis using peptidomimetic inhibitors and homology modeling. Majer F, Pavlícková L, Majer P, Hradilek M, Dolejsí E, Hrusková-Heidingsfeldová O, Pichová I. Biol. Chem. 387 1247-1254 (2006)
  31. Atomic resolution crystal structure of Sapp2p, a secreted aspartic protease from Candida parapsilosis. Dostál J, Pecina A, Hrušková-Heidingsfeldová O, Marečková L, Pichová I, Řezáčová P, Lepšík M, Brynda J. Acta Crystallogr. D Biol. Crystallogr. 71 2494-2504 (2015)
  32. Insight into the structural similarity between HIV protease and secreted aspartic protease-2 and binding mode analysis of HIV-Candida albicans inhibitors. Calugi C, Guarna A, Trabocchi A. J Enzyme Inhib Med Chem 28 936-943 (2013)
  33. Sequence Variation of Candida albicans Sap2 Enhances Fungal Pathogenicity via Complement Evasion and Macrophage M2-Like Phenotype Induction. Lin L, Wang M, Zeng J, Mao Y, Qin R, Deng J, Ouyang X, Hou X, Sun C, Wang Y, Cai Y, Li M, Tian C, Zhou X, Zhang M, Fan H, Mei H, Sarapultsev A, Wang H, Zhang G, Zipfel PF, Hu Y, Hu D, Luo S. Adv Sci (Weinh) 10 e2206713 (2023)
  34. Antimicrobial Potential of Betulinic Acid and Investigation of the Mechanism of Action against Nuclear and Metabolic Enzymes with Molecular Modeling. Rodrigues GCS, Dos Santos Maia M, de Souza TA, de Oliveira Lima E, Dos Santos LECG, Silva SL, da Silva MS, Filho JMB, da Silva Rodrigues Junior V, Scotti L, Scotti MT. Pathogens 12 449 (2023)
  35. Novel non-peptidic small molecule inhibitors of secreted aspartic protease 2 (SAP2) for the treatment of resistant fungal infections. Dong G, Liu Y, Wu Y, Tu J, Chen S, Liu N, Sheng C. Chem. Commun. (Camb.) 54 13535-13538 (2018)
  36. Using COVID-19 as a teaching tool in a time of remote learning: A workflow for bioinformatic approaches to identifying candidates for therapeutic and vaccine development. Bryce S, Heath KN, Issi L, Ryder EF, P Rao R. Biochem Mol Biol Educ 48 492-498 (2020)


Related citations provided by authors (1)

  1. Crystallization of inhibited aspartic proteinase from Candida albicans.. Cutfield S, Marshall C, Moody P, Sullivan P, Cutfield J J Mol Biol 234 1266-9 (1993)

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