8BJE

A structure of the truncated LpMIP with bound inhibitor JK236.

8BJE の概要

• エントリーDOI: 10.2210/pdb8bje/pdb
• 分子名称: Peptidyl-prolyl cis-trans isomerase, GLYCEROL, (1~{S},5~{S},6~{R})-10-[3,5-bis(chloranyl)phenyl]sulfonyl-5-(hydroxymethyl)-3-[(1~{S})-1-pyridin-2-ylethyl]-3,10-diazabicyclo[4.3.1]decan-2-one, ... (4 entities in total)
• 機能のキーワード: macrophage, potentiator, soluble, protein., structural protein
• 由来する生物種: Legionella pneumophila
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 14914.88

構造登録者

Whittaker, J.J.,Guskov, A.,Goretzki, B.,Hellmich, U.A. (登録日: 2022-11-04, 公開日: 2023-09-06, 最終更新日: 2023-09-13)

主引用文献

Wiedemann, C.,Whittaker, J.J.,Perez Carrillo, V.H.,Goretzki, B.,Dajka, M.,Tebbe, F.,Harder, J.M.,Krajczy, P.R.,Joseph, B.,Hausch, F.,Guskov, A.,Hellmich, U.A.
Legionella pneumophila macrophage infectivity potentiator protein appendage domains modulate protein dynamics and inhibitor binding.
Int.J.Biol.Macromol., 252:126366-126366, 2023

PubMed Abstract: Macrophage infectivity potentiator (MIP) proteins are widespread in human pathogens including Legionella pneumophila, the causative agent of Legionnaires' disease and protozoans such as Trypanosoma cruzi. All MIP proteins contain a FKBP (FK506 binding protein)-like prolyl-cis/trans-isomerase domain that hence presents an attractive drug target. Some MIPs such as the Legionella pneumophila protein (LpMIP) have additional appendage domains of mostly unknown function. In full-length, homodimeric LpMIP, the N-terminal dimerization domain is linked to the FKBP-like domain via a long, free-standing stalk helix. Combining X-ray crystallography, NMR and EPR spectroscopy and SAXS, we elucidated the importance of the stalk helix for protein dynamics and inhibitor binding to the FKBP-like domain and bidirectional crosstalk between the different protein regions. The first comparison of a microbial MIP and a human FKBP in complex with the same synthetic inhibitor was made possible by high-resolution structures of LpMIP with a [4.3.1]-aza-bicyclic sulfonamide and provides a basis for designing pathogen-selective inhibitors. Through stereospecific methylation, the affinity of inhibitors to L. pneumophila and T. cruzi MIP was greatly improved. The resulting X-ray inhibitor-complex structures of LpMIP and TcMIP at 1.49 and 1.34 Å, respectively, provide a starting point for developing potent inhibitors against MIPs from multiple pathogenic microorganisms.

PubMed: 37633566
DOI: 10.1016/j.ijbiomac.2023.126366

実験手法

X-RAY DIFFRACTION (1.49 Å)