XFEL and NMR Structures of Francisella Lipoprotein Reveal Conformational Space of Drug Target against Tularemia.
Anti-Bacterial Agents
/ chemistry
Crystallography, X-Ray
/ methods
Databases, Pharmaceutical
Drug Evaluation, Preclinical
/ methods
Francisella tularensis
/ chemistry
Humans
Hydrophobic and Hydrophilic Interactions
Lasers
Lipoproteins
/ antagonists & inhibitors
Molecular Dynamics Simulation
Molecular Targeted Therapy
Nuclear Magnetic Resonance, Biomolecular
Protein Conformation
Tularemia
/ drug therapy
Virulence Factors
/ chemistry
Francisella tularensis
NMR spectroscopy
X-ray crystallography
computational chemistry
drug discovery
intergrative modeling
molecular biophysics
serial femtosecond crystallography
Journal
Structure (London, England : 1993)
ISSN: 1878-4186
Titre abrégé: Structure
Pays: United States
ID NLM: 101087697
Informations de publication
Date de publication:
05 05 2020
05 05 2020
Historique:
received:
29
07
2019
revised:
23
12
2019
accepted:
13
02
2020
pubmed:
7
3
2020
medline:
11
6
2021
entrez:
7
3
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32142641
pii: S0969-2126(20)30046-0
doi: 10.1016/j.str.2020.02.005
pmc: PMC9014820
mid: NIHMS1589210
pii:
doi:
Substances chimiques
Anti-Bacterial Agents
0
Lipoproteins
0
Virulence Factors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
540-547.e3Subventions
Organisme : NIGMS NIH HHS
ID : P41 GM103393
Pays : United States
Organisme : NCRR NIH HHS
ID : P41 RR001209
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM095583
Pays : United States
Organisme : NIGMS NIH HHS
ID : U54 GM094599
Pays : United States
Informations de copyright
Published by Elsevier Ltd.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.
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