Under conditions of extremely low pH, in addition to transporting lysine, the lysine-specific permease (LysP) interacts with the transcriptional regulator CadC to upregulate cadBA operon expression. cadBA encodes CadA, which decarboxylates lysine to cadaverine, and CadB, which exports the alkaline product (cadaverine) to the environment to reduce acidity. This process is crucial for bacterial survival in the host. Here, we report the inward-open occluded Cryo-EM structure of Pseudomonas aeruginosa LysP bound to L-lysine and in complex with a nanobody at 3.7 Å resolution. The amine group of L-lysine is coordinated by hydrophobic stacking, cation-π interaction and hydrogen bonding mostly with polar uncharged amino acids. LysP reconstituted into liposomes showed robust and specific transport for tritiated L-lysine with the transport being inhibited by thialysine (S-2-aminoethyl-L-cysteine). These findings inform our understanding of the specific recognition, inhibition and transport mechanism of L-lysine by Lys, which will have important ramifications for the design of antibiotics to target bacterial LysP.
Structural insights into the lysine-specific uptake mechanism for extremely low pH regulation by bacteria
Topic
Date: 31 January 2024, 4:00 pm
Speaker
Emmanuel Nji, MSc. MGH. PhD.
CEO & Co-founder BioStruct-Africa
Wellcome Trust Int’ Intermediate Research Fellow
Strathmore University, Nairobi, Kenya
Centre for Research in Therapeutic Sciences (CREATES)
About
Dr. Nji obtained his undergraduate degree in Biochemistry from Buea University in Cameroon in 2004. He then carried out a Master’s thesis that enabled him to enhance his skills in membrane protein structural and functional biology at Imperial College London.
He competitively secured funding for PhD studies in Trinity College Dublin which he completed successfully in 2013. He then moved to Stockholm University, Confo Therapeutics, Brussels and University of Bordeaux as a postdoc.
Dr. Nji has always retained a strong vision for supporting the training of African scientists back on the continent. Whilst in Stockholm, he co-founded and still currently leads a non-profit organisation called BioStruct-Africa (www.biostructafrica.org), which brings together an international faculty of well-respected structural biologists who come together to organise workshops for Africa-based scientists to build capacity in structural biology.
He is currently a Wellcome Trust International Intermediate Research Fellow. His research is focused on implementing good laboratory practice to elucidate the atomic structures and functions of membrane transport proteins relevant to animal, human, and plant diseases and gaining insights into how these molecular machines work, which will aid in the rational design of new drugs as well guide in the optimisation of existing medicines.
To facilitate this process, he is actively involved in developing new tools for screening lipids, antibodies, and ligands in a high-throughput manner essential for the structural determination of membrane proteins by X-ray crystallography and cryogenic electron microscopy.
Selected recent publications
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