# Biophysical understanding of pathogen-host membrane protein interactions for drug discovery and delivery

> **NIH NIH R35** · UNIVERSITY OF VIRGINIA · 2024 · $435,032

## Abstract

Project Summary
Bacterial pathogens membrane proteins are important, and sometimes critical, to pathogenesis and, thus,
human health. Despite the importance of these proteins in regulating host interactions, they are less
understood than channels, transporters and GPCRs. The study of these proteins can, therefore, provide new
knowledge about membrane protein structure, function, and dynamics, as well as have impact on combatting
bacterial infections. These studies are particularly important because bacterial membrane proteins are frequent
targets of antibiotics for which resistance is a growing threat. This MIRA application outlines our recent
endeavors in understanding two bacterial membrane proteins: Opa and LspA, each of which is independently
important for bacterial proliferation in humans. The overall goal of this proposal is to determine how these
proteins look (beyond static structure), how they work, and how we can use this structure/function knowledge
to advance our understanding of bacterial pathogenesis and human health. The outer membrane Opa proteins
from Neisseria gonorrhoeae and N. meningitidis bind various host receptors and induce bacterial engulfment
into human host cells. We have previously determined the monomeric structure of Opa60 and established that
Opa-reconstituted liposomes engage in receptor-mediated phagocytosis. Future directions focus on a
multidisciplinary approach to understanding the oligomeric structure of Opa60 and the Opa60-receptor complex.
In another avenue of research, we focus on LspA, a membrane-embedded signal peptidase that processes
essential lipoproteins in nearly all bacteria. Despite the relevance of LspA as a target for antibiotics, inhibitors
of LspA are currently unavailable in the clinic. Interactions between LspA and its substrate differ among
bacterial species, and we aim to investigate the structure and conformational changes of LspA with substrate
and investigate the molecular determinants for substrate selectivity. Finally, this proposal outlines an emerging
project that investigates bacterial membrane protein – lipid interactions. Bacterial inner membrane lipid
composition varies significantly between bacterial species and the hypothesis that membrane proteins evolve
and adapt to these lipid composition is tested.Results of the proposed aims will provide the molecular
determinants of (i) neisserial Opa – Opa and Opa – host receptor interactions, (ii) substrate binding and
recognition of LspA and (iii) membrane protein – lipid interactions. This knowledge will enhance our
understanding of host-pathogen interactions and aid in combatting infections associated with bacterial
pathogens.

## Key facts

- **NIH application ID:** 10841823
- **Project number:** 2R35GM131829-06
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Linda M Columbus
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $435,032
- **Award type:** 2
- **Project period:** 2019-05-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841823

## Citation

> US National Institutes of Health, RePORTER application 10841823, Biophysical understanding of pathogen-host membrane protein interactions for drug discovery and delivery (2R35GM131829-06). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10841823. Licensed CC0.

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