Anthrax toxin lethal factor domain 3 is highly mobile and responsive to ligand binding
Kimberly M Maize1, Elbek K Kurbanov1, Teresa De La Mora-Rey1
1Department of Medicinal Chemistry and Minnesota Supercomputing Institute, University of Minnesota, 8-101 Weaver-Densford Hall, 308 Harvard Street SE, Minneapolis, MN 55455, USA.
Acta Crystallographica. Section D, Biological Crystallography
|November 6, 2014
Summary
Anthrax lethal factor (LF) adopts distinct conformations, influencing its interaction with substrates and inhibitors. Understanding these structural states is key to developing targeted therapies against anthrax toxin.
Area of Science:
- Biochemistry
- Structural Biology
- Immunology
Background:
- Anthrax toxin, composed of protective antigen (PA), edema factor (EF), and lethal factor (LF), is a critical virulence factor.
- Lethal factor (LF) is a zinc metalloproteinase that disrupts host immunity by cleaving mitogen-activated protein kinase kinases (MAPKKs) in macrophages.
Purpose of the Study:
- To investigate the conformational dynamics of lethal factor (LF) in response to ligand binding.
- To identify and characterize distinct structural states of LF relevant to its enzymatic activity and inhibition.
Main Methods:
- X-ray crystallography was employed to determine multiple LF structures, including complexes with co-crystallized inhibitors.
- Comparative analysis of diverse LF structures to identify recurring conformational states.
Main Results:
- Three predominant LF conformational states were identified: 'bioactive', 'open', and 'tight'.
- The 'bioactive' state, observed with large peptide substrates, provides open access to recognition subsites.
- The 'tight' state, seen in unliganded or small-molecule bound structures, restricts access to subsites due to domain clamping, potentially representing the lowest energy conformation.
Conclusions:
- LF exhibits significant conformational flexibility, transitioning between distinct states based on ligand presence and type.
- These conformational states directly impact LF's substrate accessibility and interaction with inhibitors.
- The identified 'tight' conformation, potentially the basal state, and ligand-induced 'open' and 'bioactive' states offer insights into LF inhibition strategies.
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