# Determining how the giant Streptococcus Pneumoniae IgA1 protease cleaves its host IgA1 substrate and how this interaction can be blocked

> **NIH NIH R21** · UNIVERSITY OF COLORADO DENVER · 2021 · $233,250

## Abstract

PROJECT SUMMARY
 Streptococcus pneumoniae (SPN) is the primary causative agent for community-acquired pneumonia in
the United States and Europe and remains the leading cause of bacterial pneumonia and meningitis in children
worldwide, making it a “major global public health problem” according to the World Health Organization. While
current vaccines target surface polysaccharides that comprise only a subset of the known serotypes, strategies
aimed against a more widely expressed protein virulence factor have been advocated, such as the SPN IgA1
Protease (IgA1P) under investigation here. However, the relatively large size of SPN IgA1P and its IgA1
substrate that it cleaves to thwart the initial host immune response has previously precluded studies aimed at
elucidating its molecular structure and interactions. By developing novel strategies through an integrative
approach that combines multiple biophysical/biochemical methods including cryo-EM, we have begun
elucidating the structure of SPN IgA1P. Remarkably, despite the presence of novel structural folds, the SPN
IgA1P active site that is formed between domains is identical to other Zn-metalloproteases and confirms our
previously published catalytic mechanism. Considering recent success in utilizing structure-based strategies
for the development of broad-based vaccines, our goals here are to provide the first high-resolution structures
of IgA1P alone, together with its IgA1 substrate, and with a first-generation monoclonal antibody (mAb) that
blocks IgA1P activity. These studies will have a major impact on how we will generate vaccines and potentially
therapeutics to block SPN infection through targeting IgA1P.
Hypothesis: The large SPN IgA1P comprises multiple independently folded subunits that forms a unique 3-
dimensional structure, which includes subunits that join to form the metalloprotease active site to properly
orient the IgA1 for hinge cleavage. Furthermore, this active site is occluded by a neutralizing mAb. We will
address this hypothesis through the following specific aims:
Aim 1) Complete the cryo-EM structure of the novel IgA1P catalytic region to determine how its
subunits interact to form the active metalloprotease.
Aim 2) Determine how IgA1P interacts with its IgA1 substrate and how this interaction is blocked by a
monoclonal antibody.

## Key facts

- **NIH application ID:** 10075228
- **Project number:** 5R21AI146295-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** ELAN Z EISENMESSER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $233,250
- **Award type:** 5
- **Project period:** 2019-12-19 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10075228

## Citation

> US National Institutes of Health, RePORTER application 10075228, Determining how the giant Streptococcus Pneumoniae IgA1 protease cleaves its host IgA1 substrate and how this interaction can be blocked (5R21AI146295-02). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10075228. Licensed CC0.

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