1eag | pdb_00001eag
Secreted aspartic proteinase (SAP2) from Candida albicans complexed with A70450
Structural highlights
FunctionCARP2_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 PubMedBACKGROUND: 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. See AlsoReferences
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