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-Structure paper
タイトル | Structural basis of colibactin activation by the ClbP peptidase. |
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ジャーナル・号・ページ | Nat Chem Biol, Vol. 19, Issue 2, Page 151-158, Year 2023 |
掲載日 | 2022年10月17日 |
![]() | José A Velilla / Matthew R Volpe / Grace E Kenney / Richard M Walsh / Emily P Balskus / Rachelle Gaudet / ![]() |
PubMed 要旨 | Colibactin, a DNA cross-linking agent produced by gut bacteria, is implicated in colorectal cancer. Its biosynthesis uses a prodrug resistance mechanism: a non-toxic precursor assembled in the ...Colibactin, a DNA cross-linking agent produced by gut bacteria, is implicated in colorectal cancer. Its biosynthesis uses a prodrug resistance mechanism: a non-toxic precursor assembled in the cytoplasm is activated after export to the periplasm. This activation is mediated by ClbP, an inner-membrane peptidase with an N-terminal periplasmic catalytic domain and a C-terminal three-helix transmembrane domain. Although the transmembrane domain is required for colibactin activation, its role in catalysis is unclear. Our structure of full-length ClbP bound to a product analog reveals an interdomain interface important for substrate binding and enzyme stability and interactions that explain the selectivity of ClbP for the N-acyl-D-asparagine prodrug motif. Based on structural and biochemical evidence, we propose that ClbP dimerizes to form an extended substrate-binding site that can accommodate a pseudodimeric precolibactin with its two terminal prodrug motifs in the two ClbP active sites, thus enabling the coordinated activation of both electrophilic warheads. |
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手法 | EM (単粒子) / X線回折 |
解像度 | 2.3 - 3.73 Å |
構造データ | EMDB-26593, PDB-7ul6: ![]() PDB-7mde: ![]() PDB-7mdf: |
化合物 | ![]() ChemComp-OLC: ![]() ChemComp-2PE: ![]() ChemComp-IMD: ![]() ChemComp-DMS: ![]() ChemComp-SO4: ![]() ChemComp-CL: ![]() ChemComp-HOH: ![]() ChemComp-Z9A: ![]() ChemComp-Z9G: ![]() ChemComp-AV0: ![]() ChemComp-97N: |
由来 |
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![]() | HYDROLASE / colibactin peptidase / S12 peptidase / HYDROLASE/INHIBITOR / HYDROLASE-INHIBITOR complex / inner-membrane hydrolase |