9OF6

Structure of the Acinetobacter baumannii Response Regulator PmrA Receiver Domain I13M Mutation in Active Dimer State

Summary for 9OF6

• Entry DOI: 10.2210/pdb9of6/pdb
• Related: 7M0S
• Descriptor: PmrA (2 entities in total)
• Functional Keywords: response regulator, two component system, polymyxin resistance, resistant mutant, transcription
• Biological source: Acinetobacter baumannii
• Total number of polymer chains: 2
• Total formula weight: 28885.45

Authors

Milton, M.E.,Jaimes, F.E.,Cavanagh, J. (deposition date: 2025-04-29, release date: 2025-11-26, Last modification date: 2025-12-10)

Primary citation

Jaimes, F.E.,Hondros, A.D.,Kinkead, J.,Milton, M.E.,Thompson, R.J.,Figg, A.M.,Melander, C.,Cavanagh, J.
PmrA Mutations in Drug-Resistant Acinetobacter baumannii Affect Sensor Kinase-Response Regulator Interaction and Phosphotransfer.
Microorganisms, 13:-, 2025

PubMed Abstract: Multi-drug resistance in poses a significant human health threat. For multidrug-resistant pathogens, 'last line of defense' antibiotics like the polymyxins are implemented. Concerningly, polymyxin-resistance is evidenced in and is mediated by the PmrAB two-component system. The response regulator PmrA upregulates , leading to lipooligosaccharide modifications that reduce polymyxin binding. Sequencing of resistant isolates has identified point mutations in the receiver domain of PmrA that correlate with increased resistance. To investigate functional impacts of these mutations, we characterized five PmrA mutations (D10N, M12I, I13M, G54E, and S119T) by assessing changes in PmrA DNA-binding affinity, dimerization, phosphorylation, and structure. Our findings suggest that these mutations impact the ability of PmrA to receive the activating phosphoryl group from the sensor kinase PmrB. The slow phosphoryl uptake is likely due to (1) disruption of the PmrB-PmrA interaction by interfering with the recognition site on PmrA, or (2) perturbation of PmrA's active site via steric hindrance or displacement of residues and ions necessary for coordination within the aspartic acid pocket. Slowed phosphorylation of a response regulator can lead to enhanced gene transcription through several mechanisms. These insights advance our understanding of PmrA-mediated resistance in .

PubMed: 41304284
DOI: 10.3390/microorganisms13112600

Experimental method

X-RAY DIFFRACTION (1.86 Å)