9QAA
Crystal structure of Borrelia burgdorferi BB0238-BB0323 complex (BB0238 residues 118-256; BB0323 residues 26-210)
Summary for 9QAA
| Entry DOI | 10.2210/pdb9qaa/pdb |
| Descriptor | LysM domain protein, BB0238 (2 entities in total) |
| Functional Keywords | protein complex, lyme disease, borreliosis., structural protein |
| Biological source | Borreliella burgdorferi B31 More |
| Total number of polymer chains | 2 |
| Total formula weight | 38617.46 |
| Authors | |
| Primary citation | Bista, S.,Brangulis, K.,Bhattachan, B.,Foor, S.D.,Ronzetti, M.H.,Jain, S.,Miller, J.,Subramanion, J.L.,Kitsou, C.,Rana, V.S.,Rai, G.,Zakharov, A.V.,Simeonov, A.,Baljinnyam, B.,Pal, U. Targeting of interaction between BB0323-BB0238 informs new paradigms in Lyme disease therapeutics. Plos Pathog., 22:e1013805-e1013805, 2026 Cited by PubMed Abstract: Borrelia burgdorferi, one of the most prevalent tick-borne pathogens, can cause a complex and multisystem illness called Lyme disease, where there has been an unmet need for novel therapeutic or preventive strategies. We previously identified an essential protein-protein interaction (PPI) event in B. burgdorferi involving two unique proteins, BB0323 and BB0238; herein, we show that this PPI is indispensable for long-term borrelial survival in mammals and explore its potential as a novel target for small molecule therapeutics. Using X-ray crystallography, we solved the structure of the BB0238-BB0323 complex and identified the hotspot residues that form the biomolecular PPI interface area of ~1000 square Ångstroms. We then performed quantitative high-throughput drug screens of 62,740 diverse small molecules utilizing an amplified luminescent proximity homogeneous assay linked immunosorbent assay (AlphaLISA). Following a comprehensive pipeline to confirm small molecule hits, we short-listed three distinct PPI inhibitors of BB0238-BB0323. One of these inhibitors, called lomibuvir (VX-222, VCH-222), displayed robust PPI inhibition inside B. burgdorferi cells and was shown to affect pathogen persistence in a tick-borne murine model of Lyme disease. Our study highlights targeted PPI disruption as a new therapeutic strategy against B. burgdorferi and may foster future antimicrobial discovery efforts to resolve clinical complications associated with Lyme disease. PubMed: 41481600DOI: 10.1371/journal.ppat.1013805 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.5 Å) |
Structure validation
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