1eag

From Proteopedia

(Difference between revisions)

Current revision

Secreted aspartic proteinase (SAP2) from Candida albicans complexed with A70450

Structural highlights

1eag is a 1 chain structure with sequence from Candida albicans. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.1Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CARP2_CANAX Secreted aspartic peptidases (SAPs) are a group of ten acidic hydrolases considered as key virulence factors (PubMed:11478679, PubMed:12761103, PubMed:15820985, PubMed:15845479, PubMed:19880183, PubMed:20713630, PubMed:22302440, PubMed:23927842). These enzymes supply the fungus with nutrient amino acids as well as are able to degrade the selected host's proteins involved in the immune defense (PubMed:11478679, PubMed:12761103, PubMed:15820985, PubMed:15845479, PubMed:19880183, PubMed:20713630, PubMed:22302440, PubMed:23927842). Induces host inflammatory cytokine production in a proteolytic activity-independent way (PubMed:20713630). Plays a role in tissue damage during superficial infection (PubMed:12761103). Moreover, acts toward human hemoglobin though limited proteolysis to generate a variety of antimicrobial hemocidins, enabling to compete with the other microorganisms of the same physiological niche using the microbicidal peptides generated from the host protein (PubMed:23927842).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] Plays a key role in defense against host by cleaving histatin-5 (Hst 5), a peptide from human saliva that carries out fungicidal activity (PubMed:27390786, PubMed:29143452, PubMed:31675138). The cleavage rate decreases in an order of SAP2 > SAP9 > SAP3 > SAP7 > SAP4 > SAP1 > SAP8 (PubMed:27390786). The first cleavage occurs between residues 'Lys-17' and 'His-18' of Hst 5, giving DSHAKRHHGYKRKFHEK and HHSHRGY peptides (PubMed:27390786). Simultaneously, the DSHAKRHHGYKRK peptide is also formed (PubMed:27390786). Further fragmentation by SAP2 results in FHEK and DSHAKRHHGY products (PubMed:27390786).^[9] ^[10] ^[11]

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

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. CONCLUSIONS: 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.

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. 1995 Nov 15;3(11):1261-71. PMID:8591036^[12]

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

References

↑ Schaller M, Januschke E, Schackert C, Woerle B, Korting HC. Different isoforms of secreted aspartyl proteinases (Sap) are expressed by Candida albicans during oral and cutaneous candidosis in vivo. J Med Microbiol. 2001 Aug;50(8):743-7. PMID:11478679
↑ Schaller M, Bein M, Korting HC, Baur S, Hamm G, Monod M, Beinhauer S, Hube B. The secreted aspartyl proteinases Sap1 and Sap2 cause tissue damage in an in vitro model of vaginal candidiasis based on reconstituted human vaginal epithelium. Infect Immun. 2003 Jun;71(6):3227-34. PMID:12761103 doi:10.1128/IAI.71.6.3227-3234.2003
↑ Copping VM, Barelle CJ, Hube B, Gow NA, Brown AJ, Odds FC. Exposure of Candida albicans to antifungal agents affects expression of SAP2 and SAP9 secreted proteinase genes. J Antimicrob Chemother. 2005 May;55(5):645-54. PMID:15820985 doi:10.1093/jac/dki088
↑ Schaller M, Korting HC, Borelli C, Hamm G, Hube B. Candida albicans-secreted aspartic proteinases modify the epithelial cytokine response in an in vitro model of vaginal candidiasis. Infect Immun. 2005 May;73(5):2758-65. PMID:15845479 doi:10.1128/IAI.73.5.2758-2765.2005
↑ Gropp K, Schild L, Schindler S, Hube B, Zipfel PF, Skerka C. The yeast Candida albicans evades human complement attack by secretion of aspartic proteases. Mol Immunol. 2009 Dec;47(2-3):465-75. PMID:19880183 doi:10.1016/j.molimm.2009.08.019
↑ Pietrella D, Rachini A, Pandey N, Schild L, Netea M, Bistoni F, Hube B, Vecchiarelli A. The Inflammatory response induced by aspartic proteases of Candida albicans is independent of proteolytic activity. Infect Immun. 2010 Nov;78(11):4754-62. PMID:20713630 doi:10.1128/IAI.00789-10
↑ Ramage G, Coco B, Sherry L, Bagg J, Lappin DF. In vitro Candida albicans biofilm induced proteinase activity and SAP8 expression correlates with in vivo denture stomatitis severity. Mycopathologia. 2012 Jul;174(1):11-19. PMID:22302440 doi:10.1007/s11046-012-9522-2
↑ Bochenska O, Rapala-Kozik M, Wolak N, Bras G, Kozik A, Dubin A, Aoki W, Ueda M, Mak P. Secreted aspartic peptidases of Candida albicans liberate bactericidal hemocidins from human hemoglobin. Peptides. 2013 Oct;48:49-58. doi: 10.1016/j.peptides.2013.07.023. Epub 2013 Aug, 6. PMID:23927842 doi:http://dx.doi.org/10.1016/j.peptides.2013.07.023
↑ Bochenska O, Rapala-Kozik M, Wolak N, Aoki W, Ueda M, Kozik A. The action of ten secreted aspartic proteases of pathogenic yeast Candida albicans on major human salivary antimicrobial peptide, histatin 5. Acta Biochim Pol. 2016;63(3):403-10. PMID:27390786 doi:10.18388/abp.2016_1318
↑ Ikonomova SP, Moghaddam-Taaheri P, Jabra-Rizk MA, Wang Y, Karlsson AJ. Engineering improved variants of the antifungal peptide histatin 5 with reduced susceptibility to Candida albicans secreted aspartic proteases and enhanced antimicrobial potency. FEBS J. 2018 Jan;285(1):146-159. PMID:29143452 doi:10.1111/febs.14327
↑ Ikonomova SP, Moghaddam-Taaheri P, Wang Y, Doolin MT, Stroka KM, Hube B, Karlsson AJ. Effects of histatin 5 modifications on antifungal activity and kinetics of proteolysis. Protein Sci. 2020 Feb;29(2):480-493. PMID:31675138 doi:10.1002/pro.3767
↑ Cutfield SM, Dodson EJ, Anderson BF, Moody PC, Marshall CJ, Sullivan PA, Cutfield JF. The crystal structure of a major secreted aspartic proteinase from Candida albicans in complexes with two inhibitors. Structure. 1995 Nov 15;3(11):1261-71. PMID:8591036

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1eag"

Categories: Candida albicans | Large Structures | Cutfield JF | Cutfield SM

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[1eag]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Candida_albicans Candida albicans]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EAG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1EAG FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A70:N-ETHYL-N-[(4-METHYLPIPERAZIN-1-YL)CARBONYL]-D-PHENYLALANYL-N-[(1S,2S,4R)-4-(BUTYLCARBAMOYL)-1-(CYCLOHEXYLMETHYL)-2-HYDROXY-5-METHYLHEXYL]-L-NORLEUCINAMIDE'>A70</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]] 2.1&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Candidapepsin Candidapepsin], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.24 3.4.23.24] </span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A70:N-ETHYL-N-[(4-METHYLPIPERAZIN-1-YL)CARBONYL]-D-PHENYLALANYL-N-[(1S,2S,4R)-4-(BUTYLCARBAMOYL)-1-(CYCLOHEXYLMETHYL)-2-HYDROXY-5-METHYLHEXYL]-L-NORLEUCINAMIDE'>A70</scene></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=1eag FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1eag OCA], [https://pdbe.org/1eag PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1eag RCSB], [https://www.ebi.ac.uk/pdbsum/1eag PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1eag ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/CARP2_CANAX CARP2_CANAX] Secreted aspartic peptidases (SAPs) are a group of ten acidic hydrolases considered as key virulence factors (PubMed:11478679, PubMed:12761103, PubMed:15820985, PubMed:15845479, PubMed:19880183, PubMed:20713630, PubMed:22302440, PubMed:23927842). These enzymes supply the fungus with nutrient amino acids as well as are able to degrade the selected host's proteins involved in the immune defense (PubMed:11478679, PubMed:12761103, PubMed:15820985, PubMed:15845479, PubMed:19880183, PubMed:20713630, PubMed:22302440, PubMed:23927842). Induces host inflammatory cytokine production in a proteolytic activity-independent way (PubMed:20713630). Plays a role in tissue damage during superficial infection (PubMed:12761103). Moreover, acts toward human hemoglobin though limited proteolysis to generate a variety of antimicrobial hemocidins, enabling to compete with the other microorganisms of the same physiological niche using the microbicidal peptides generated from the host protein (PubMed:23927842).<ref>PMID:11478679</ref> <ref>PMID:12761103</ref> <ref>PMID:15820985</ref> <ref>PMID:15845479</ref> <ref>PMID:19880183</ref> <ref>PMID:20713630</ref> <ref>PMID:22302440</ref> <ref>PMID:23927842</ref>   Plays a key role in defense against host by cleaving histatin-5 (Hst 5), a peptide from human saliva that carries out fungicidal activity (PubMed:27390786, PubMed:29143452, PubMed:31675138). The cleavage rate decreases in an order of SAP2 > SAP9 > SAP3 > SAP7 > SAP4 > SAP1 > SAP8 (PubMed:27390786). The first cleavage occurs between residues 'Lys-17' and 'His-18' of Hst 5, giving DSHAKRHHGYKRKFHEK and HHSHRGY peptides (PubMed:27390786). Simultaneously, the DSHAKRHHGYKRK peptide is also formed (PubMed:27390786). Further fragmentation by SAP2 results in FHEK and DSHAKRHHGY products (PubMed:27390786).<ref>PMID:27390786</ref> <ref>PMID:29143452</ref> <ref>PMID:31675138</ref>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 13: / Line 15: @@
   <jmolCheckbox>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ea/1eag_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>
   </jmolCheckbox>
@@ Line 30: / Line 32: @@
 ==See Also==
 *[[Pepsin|Pepsin]]
-*[[Proteinase|Proteinase]]
 *[[Proteinase 3D structures|Proteinase 3D structures]]
 == References ==
@@ Line 37: / Line 38: @@
 </StructureSection>
 [[Category: Candida albicans]]
-[[Category: Candidapepsin]]
 [[Category: Large Structures]]
-[[Category: Cutfield, J F]]
+[[Category: Cutfield JF]]
-[[Category: Cutfield, S M]]
+[[Category: Cutfield SM]]
-[[Category: Aspartic protease]]
-[[Category: Candida albican]]
-[[Category: Hydrolase-hydrolase inhibitor complex]]
-[[Category: Sap2]]

1eag

From Proteopedia

Current revision

Secreted aspartic proteinase (SAP2) from Candida albicans complexed with A70450

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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