Clevenger Kenneth D, Mascarenhas Romila, Catlin Daniel, Wu Rui, Kelleher Neil L, Drake Eric J, Gulick Andrew M, Liu Dali, Fast Walter
Department of Chemistry, Northwestern University , Evanston, Illinois 60208, United States.
Department of Chemistry and Biochemistry, Loyola University Chicago , Chicago, Illinois 60660, United States.
ACS Chem Biol. 2017 Mar 17;12(3):643-647. doi: 10.1021/acschembio.7b00031. Epub 2017 Feb 15.
Siderophore biosynthesis by Pseudomonas aeruginosa enhances virulence and represents an attractive drug target. PvdQ functions in the type-1 pyoverdine biosynthetic pathway by removing a myristoyl anchor from a pyoverdine precursor, allowing eventual release from the periplasm. A circularly permuted version of PvdQ bypasses the self-processing step of this Ntn-hydrolase and retains the activity, selectivity, and structure of wild-type PvdQ, as revealed by a 1.8 Å resolution X-ray crystal structure. A 2.55 Å resolution structure of the inactive S1A/N269D-cpPvdQ mutant in complex with the pyoverdine precursor PVDIq reveals a specific binding pocket for the d-Tyr of this modified peptide substrate. To our knowledge, this structure is the first of a pyoverdine precursor peptide bound to a biosynthetic enzyme. Details of the observed binding interactions have implications for control of pyoverdine biosynthesis and inform future drug design efforts.
铜绿假单胞菌的铁载体生物合成增强了毒力，是一个有吸引力的药物靶点。PvdQ在1型绿脓菌素生物合成途径中发挥作用，通过从绿脓菌素前体中去除肉豆蔻酰锚定基团，使绿脓菌素最终从周质中释放出来。如分辨率为1.8 Å的X射线晶体结构所示，PvdQ的环状排列版本绕过了这种Ntn水解酶的自加工步骤，并保留了野生型PvdQ的活性、选择性和结构。与绿脓菌素前体PVDIq结合的无活性S1A/N269D-cpPvdQ突变体的分辨率为2.55 Å的结构揭示了这种修饰肽底物的d-Tyr的一个特定结合口袋。据我们所知，该结构是与生物合成酶结合的绿脓菌素前体肽的首个结构。观察到的结合相互作用的细节对绿脓菌素生物合成的控制具有重要意义，并为未来的药物设计工作提供了参考。
