6P55

Crystal structure of transpeptidase domain of PBP2 from Neisseria gonorrhoeae acylated by cefixime

6P55 の概要

• エントリーDOI: 10.2210/pdb6p55/pdb
• 分子名称: peptidoglycan D,D-transpeptidase PenA, cefixime, bound form, PHOSPHATE ION, ... (5 entities in total)
• 機能のキーワード: penicillin-binding protein, transpeptidase domain, neisseria gonorrhoeae, antibiotic resistance, hydrolase-antibiotic complex, hydrolase/antibiotic
• 由来する生物種: Neisseria gonorrhoeae
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 72166.73

構造登録者

Singh, A.,Davies, C. (登録日: 2019-05-29, 公開日: 2019-08-07, 最終更新日: 2024-11-13)

主引用文献

Singh, A.,Tomberg, J.,Nicholas, R.A.,Davies, C.
Recognition of the beta-lactam carboxylate triggers acylation ofNeisseria gonorrhoeaepenicillin-binding protein 2.
J.Biol.Chem., 294:14020-14032, 2019

PubMed Abstract: Resistance of to extended-spectrum cephalosporins (ESCs) has become a major threat to human health. The primary mechanism by which becomes resistant to ESCs is by acquiring a mosaic allele, encoding penicillin-binding protein 2 (PBP2) variants containing up to 62 mutations compared with WT, of which a subset contribute to resistance. To interpret molecular mechanisms underpinning cephalosporin resistance, it is necessary to know how PBP2 is acylated by ESCs. Here, we report the crystal structures of the transpeptidase domain of WT PBP2 in complex with cefixime and ceftriaxone, along with structures of PBP2 in the form and with a phosphate ion bound in the active site at resolutions of 1-7-1.9 Å. These structures reveal that acylation of PBP2 by ESCs is accompanied by rotation of the Thr-498 side chain in the KTG motif to contact the cephalosporin carboxylate, twisting of the β3 strand to form the oxyanion hole, and rolling of the β3-β4 loop toward the active site. Recognition of the cephalosporin carboxylate appears to be the key trigger for formation of an acylation-competent state of PBP2. The structures also begin to explain the impact of mutations implicated in ESC resistance. In particular, a G545S mutation may hinder twisting of β3 because its side chain hydroxyl forms a hydrogen bond with Thr-498. Overall, our data suggest that acylation is initiated by conformational changes elicited or trapped by binding of ESCs and that these movements are restricted by mutations associated with resistance against ESCs.

PubMed: 31362987
DOI: 10.1074/jbc.RA119.009942

実験手法

X-RAY DIFFRACTION (1.74 Å)