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Crystal structures of the LsrR proteins complexed with phospho-AI-2 and two signal-interrupting analogues reveal distinct mechanisms for ligand recognition.

Ha JH, Eo Y, Grishaev A, Guo M, Smith JA, Sintim HO, Kim EH, Cheong HK, Bentley WE, Ryu KS
J Am Chem Soc 135 15526-35 (2013)
Related entries: 4l4y, 4l4z, 4l50, 4l51, 4l5j

Cited: 14 times
EuropePMC logo PMID: 24047255

Abstract

Quorum sensing (QS) is a cell-to-cell communication system responsible for a variety of bacterial phenotypes including virulence and biofilm formation. QS is mediated by small molecules, autoinducers (AIs), including AI-2 that is secreted by both Gram-positive and -negative microbes. LsrR is a key transcriptional regulator that governs the varied downstream processes by perceiving AI-2 signal, but its activation via autoinducer-binding remains poorly understood. Here, we provide detailed regulatory mechanism of LsrR from the crystal structures in complexes with the native signal (phospho-AI-2, D5P) and two quorum quenching antagonists (ribose-5-phosphate, R5P; phospho-isobutyl-AI-2, D8P). Interestingly, the bound D5P and D8P molecules are not the diketone forms but rather hydrated, and the hydrated moiety forms important H-bonds with the carboxylate of D243. The D5P-binding flipped out F124 of the binding pocket, and resulted in the disruption of the dimeric interface-1 by unfolding the α7 segment. However, the same movement of F124 by the D8P'-binding did not cause the unfolding of the α7 segment. Although the LsrR-binding affinity of R5P (Kd, ∼1 mM) is much lower than that of D5P and D8P (∼2.0 and ∼0.5 μM), the α-anomeric R5P molecule fits into the binding pocket without any structural perturbation, and thus stabilizes the LsrR tetramer. The binding of D5P, not D8P and R5P, disrupted the tetrameric structure and thus is able to activate LsrR. The detailed structural and mechanistic insights from this study could be useful for facilitating design of new antivirulence and antibiofilm agents based on LsrR.

Articles - 4l5i mentioned but not cited (1)

  1. Crystal structures of the LsrR proteins complexed with phospho-AI-2 and two signal-interrupting analogues reveal distinct mechanisms for ligand recognition. Ha JH, Eo Y, Grishaev A, Guo M, Smith JA, Sintim HO, Kim EH, Cheong HK, Bentley WE, Ryu KS. J Am Chem Soc 135 15526-15535 (2013)


Reviews citing this publication (2)

  1. Mechanisms of Inhibition of Quorum Sensing as an Alternative for the Control of E. coli and Salmonella. Escobar-Muciño E, Arenas-Hernández MMP, Luna-Guevara ML. Microorganisms 10 884 (2022)
  2. Antimicrobial Resistance and Recent Alternatives to Antibiotics for the Control of Bacterial Pathogens with an Emphasis on Foodborne Pathogens. Helmy YA, Taha-Abdelaziz K, Hawwas HAE, Ghosh S, AlKafaas SS, Moawad MMM, Saied EM, Kassem II, Mawad AMM. Antibiotics (Basel) 12 274 (2023)

Articles citing this publication (11)

  1. Evidence of link between quorum sensing and sugar metabolism in Escherichia coli revealed via cocrystal structures of LsrK and HPr. Ha JH, Hauk P, Cho K, Eo Y, Ma X, Stephens K, Cha S, Jeong M, Suh JY, Sintim HO, Bentley WE, Ryu KS. Sci Adv 4 eaar7063 (2018)
  2. LsrF, a coenzyme A-dependent thiolase, catalyzes the terminal step in processing the quorum sensing signal autoinducer-2. Marques JC, Oh IK, Ly DC, Lamosa P, Ventura MR, Miller ST, Xavier KB. Proc Natl Acad Sci U S A 111 14235-14240 (2014)
  3. Directed assembly of a bacterial quorum. Servinsky MD, Terrell JL, Tsao CY, Wu HC, Quan DN, Zargar A, Allen PC, Byrd CM, Sund CJ, Bentley WE. ISME J 10 158-169 (2016)
  4. Tackling Antimicrobial Resistance with Small Molecules Targeting LsrK: Challenges and Opportunities. Linciano P, Cavalloro V, Martino E, Kirchmair J, Listro R, Rossi D, Collina S. J Med Chem 63 15243-15257 (2020)
  5. A Versatile Strategy for the Synthesis of 4,5-Dihydroxy-2,3-Pentanedione (DPD) and Related Compounds as Potential Modulators of Bacterial Quorum Sensing. Stotani S, Gatta V, Medda F, Padmanaban M, Karawajczyk A, Tammela P, Giordanetto F, Tzalis D, Collina S. Molecules 23 E2545 (2018)
  6. Geminal dihalogen isosteric replacement in hydrated AI-2 affords potent quorum sensing modulators. Guo M, Zheng Y, Terell JL, Ad M, Opoku-Temeng C, Bentley WE, Sintim HO. Chem Commun (Camb) 51 2617-2620 (2015)
  7. Glycation Reactivity of a Quorum-Sensing Signaling Molecule. Tsuchikama K, Gooyit M, Harris TL, Zhu J, Globisch D, Kaufmann GF, Janda KD. Angew Chem Int Ed Engl 55 4002-4006 (2016)
  8. Increasing the soluble expression and crystallization of the Escherichia coli quorum-sensing protein LsrK. Ha JH, Eo Y, Ahn HC, Ryu KS. Acta Crystallogr F Struct Biol Commun 73 253-258 (2017)
  9. Mathematical model of LsrR-binding and derepression in Escherichia coli K12. Graff SM, Bentley WE. J Bioinform Comput Biol 15 1650039 (2017)
  10. Structural Insights into the Ligand-LsrK Kinase Binding Mode: A Step Forward in the Discovery of Novel Antimicrobial Agents. Listro R, Milli G, Pellegrini A, Motta C, Cavalloro V, Martino E, Kirchmair J, Pietrocola G, Rossi D, Linciano P, Collina S. Molecules 28 2542 (2023)
  11. Neuromodulators as Interdomain Signaling Molecules Capable of Occupying Effector Binding Sites in Bacterial Transcription Factors. Purtov YA, Ozoline ON. Int J Mol Sci 24 15863 (2023)


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