# STRUCTURAL STUDIES OF MOLECULAR PATHOGENESIS

> **NIH NIH R01** · UNIVERSITY OF COLORADO · 1987 · $108,844

## Abstract

In recent years, several exotoxin systems involved in bacterial
pathogenesis--specifically, those exotoxins which translocate across target
eukaryotic cell membranes into the cytoplasm, and which modify specific
intracellular targets--have been well-characterized.  These exotoxins,
which are major determinants of pathogenicity in bacterial infections,
offer potential systems (i) for understanding the receptor binding,
membrane translocation, and enzymatic activation mechanisms shared by
bacterial exotoxins from diverse sources; (ii) for developing immunizations
against specific toxins; (iii) for constructing targeted cytotoxic agents.

Despite the potential contribution of protein crystallography to
understanding these systems, little three-dimensional structural
information is available for members of this class of toxins.  The recent
3.0 angstroms structure from this laboratory of Pseudomonas aeruginosa
exotoxin A, a major determinant of lethality in P. aeruginosa infections,
is currently the only available molecular model of a bacterial exotoxin.

Structural work on exotoxin A will be extended.  To produce a precise
molecular model, data will be collected to approximately 2.0-2.2 angstroms
resolution and the current model refined.  Structural and biochemical
experiments will be effected to define (i) the receptor binding domain,
(ii) the membrane translocation mechanism, and (iii) the enzymatic
mechanism of exotoxin A.

In addition, crystallographic work on the three-protein exotoxin system of
Bacillus anthracis, the pathogen responsible for anthrax disease, has been
initiated.  Two proteins of the system--the protective antigen and the
lethal factor--have been crystallized.  The protective antigen crystals
diffract to approximately 3.0 angstroms resolution; an effort to determine
the structure of the molecule is underway.  Suitability of crystal forms of
lethal factor for high resolution x-ray crystallograhic work is being
examined.

The exotoxin A portion of this proposal is a continuation of work
accomplished under "Three-Dimensional Structure of Pseudomonas Toxin"; it
is discussed in that context.  The current proposal is directed toward
mechanisms of exotoxins in general, including but not confined to exotoxin
A.

## Key facts

- **NIH application ID:** 3129167
- **Project number:** 5R01AI019762-06
- **Recipient organization:** UNIVERSITY OF COLORADO
- **SAM.gov UEI:** SPVKK1RC2MZ3
- **Principal Investigator:** David B McKay
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1987
- **Award amount:** $108,844
- **Award type:** 5
- **Project period:** 1982-09-01 → 1988-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3129167

## Citation

> US National Institutes of Health, RePORTER application 3129167, STRUCTURAL STUDIES OF MOLECULAR PATHOGENESIS (5R01AI019762-06). Retrieved via MORVS 2026-10-24 from https://api.morvs.ai/grant/nih/3129167. Licensed CC0.

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