NIH grant: Uncovering interactions of the atypical lipid transporter Rv1410c with its substrates and the lipid carrier LprG in Mycobacterium tuberculosis (1R21AI193818-01A1)

retained text

NIH grant 1R21AI193818-01A1: Uncovering interactions of the atypical lipid transporter Rv1410c with its substrates and the lipid carrier LprG in Mycobacterium tuberculosis
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Jessica Chuang Seeliger. Award: $466199.
Start: 2026-06-24T00:00:00.
SUMMARY
The human pathogen Mycobacterium tuberculosis still causes an estimated 1.3 million deaths each year
worldwide due to tuberculosis. The integral membrane transporter Rv1410c and its periplasmic partner LprG
are required for Mtb virulence and have been implicated in the transport of lipids across the Mtb plasma
membrane, as part of the synthesis and maintenance of the cell wall. Rv1410c belongs to the major facilitator
superfamily of transporters and is one of the few examples of bacterial lipid transporters driven by the protein
gradient. While there is moderate-resolution structural information for a homologue from another
mycobacterium, key mechanistic questions about Rv1410c remain unanswered, including (1) how protonation
induces conformational changes and (2) how lipids are recognized and transferred to the likely downstream
lipid carrier protein LprG. We hypothesize that Rv1410c proceeds through a reaction cycle in which protonation
triggers conformational transition via salt-bridge breakage and substrate-bound conformations promote
interaction with and substrate transfer to LprG. We will test this hypothesis using cryo-EM structure
determination and protein crosslinking within the native environment of live cells to discover and validate the
binding sites and functionally important residues for (1) lipid substrates and (2) LprG. Our proposal is
supported by initial studies that have already yielded cryo-EM apo structures and validated new protein-lipid
crosslinking methods in mycobacteria. The expected results will inform the reaction mechanism for transport by
Rv1410c and more generally, prediction of physiological function for MFS transporters. This knowledge will
open opportunities for specific inhibition of this virulence determinant in Mtb and strategies for targeting MFS
transporters in other pathogens.

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