Medical College of Wisconsin
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XFEL and NMR Structures of Francisella Lipoprotein Reveal Conformational Space of Drug Target against Tularemia. Structure 2020 May 05;28(5):540-547.e3

Date

03/07/2020

Pubmed ID

32142641

Pubmed Central ID

PMC9014820

DOI

10.1016/j.str.2020.02.005

Scopus ID

2-s2.0-85083862415 (requires institutional sign-in at Scopus site)   8 Citations

Abstract

Francisella tularensis is the causative agent for the potentially fatal disease tularemia. The lipoprotein Flpp3 has been identified as a virulence determinant of tularemia with no sequence homology outside the Francisella genus. We report a room temperature structure of Flpp3 determined by serial femtosecond crystallography that exists in a significantly different conformation than previously described by the NMR-determined structure. Furthermore, we investigated the conformational space and energy barriers between these two structures by molecular dynamics umbrella sampling and identified three low-energy intermediate states, transitions between which readily occur at room temperature. We have also begun to investigate organic compounds in silico that may act as inhibitors to Flpp3. This work paves the road to developing targeted therapeutics against tularemia and aides in our understanding of the disease mechanisms of tularemia.

Author List

Zook J, Shekhar M, Hansen D, Conrad C, Grant T, Gupta C, White T, Barty A, Basu S, Zhao Y, Zatsepin N, Ishchenko A, Batyuk A, Gati C, Li C, Galli L, Coe J, Hunter M, Liang M, Weierstall U, Nelson G, James D, Stauch B, Craciunescu F, Thifault D, Liu W, Cherezov V, Singharoy A, Fromme P

Author

Wei Liu PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Anti-Bacterial Agents
Crystallography, X-Ray
Databases, Pharmaceutical
Drug Evaluation, Preclinical
Francisella tularensis
Humans
Hydrophobic and Hydrophilic Interactions
Lasers
Lipoproteins
Molecular Dynamics Simulation
Molecular Targeted Therapy
Nuclear Magnetic Resonance, Biomolecular
Protein Conformation
Tularemia
Virulence Factors