期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 288, 期 20, 页码 14287-14296出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.444927
关键词
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资金
- ESRF
- European agency (Polish Ministry of Science and Higher Education) [137/7.PR-EU/2011/2]
- United States agency (Polish Ministry of Science and Higher Education) [137/7.PR-EU/2011/2]
- Polish agency (Polish Ministry of Science and Higher Education) [137/7.PR-EU/2011/2]
- Spanish agency (Polish Ministry of Science and Higher Education) [137/7.PR-EU/2011/2]
- Catalan agency (Polish Ministry of Science and Higher Education) [137/7.PR-EU/2011/2]
- Foundation for Polish Science TEAM Project [DPS/424-329/10]
- National Institutes of Health from the NIDCR [DE 09761, DE 022597]
- Polish National Science Center [2011/01/B/NZ6/00268, 2012/04/A/NZ1/00051]
- European Union [FP7-HEALTH-F3-2009-223101, FP7-PEOPLE-2011-ITN-290246, FP7-HEALTH-2010-261460]
- Spanish Ministry of Economy and Competitivity [BIO2009-10334, BFU2012-32862, CSD2006-00015]
- Fundacio La Marato de TV3 Grant [2009-100732]
- Catalan National Government AGAUR Grant [2009SGR1036]
Zymogenicity is a regulatory mechanism that prevents inadequate catalytic activity in the wrong context. It plays a central role in maintaining microbial virulence factors in an inactive form inside the pathogen until secretion. Among these virulence factors is the cysteine peptidase gingipain B (RgpB), which is the major virulence factor secreted by the periodontopathogen Porphyromonas gingivalis that attacks host vasculature and defense proteins. The structure of the complex between soluble mature RgpB, consisting of a catalytic domain and an immunoglobulin superfamily domain, and its 205-residue N-terminal prodomain, the largest structurally characterized to date for a cysteine peptidase, reveals a novel fold for the prodomain that is distantly related to sugar-binding lectins. It attaches laterally to the catalytic domain through a large concave surface. The main determinant for latency is a surface inhibitory loop, which approaches the active-site cleft of the enzyme on its non-primed side in a substrate-like manner. It inserts an arginine (Arg(126)) into the S-1 pocket, thus matching the substrate specificity of the enzyme. Downstream of Arg(126), the polypeptide leaves the cleft, thereby preventing cleavage. Moreover, the carbonyl group of Arg(126) establishes a very strong hydrogen bond with the co-catalytic histidine, His(440), pulling it away from the catalytic cysteine, Cys(473), and toward Glu(381), which probably plays a role in orienting the side chain of His(440) during catalysis. The present results provide the structural determinants of zymogenic inhibition of RgpB by way of a novel inhibitory mechanism for peptidases in general and open the field for the design of novel inhibitory strategies in the treatment of human periodontal disease.
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