4PKS

Anthrax toxin lethal factor with bound small molecule inhibitor 11

Summary for 4PKS

• Entry DOI: 10.2210/pdb4pks/pdb
• Related: 1J7N 1JKY 1PWP 1PWQ 1PWU 1PWV 1PWW 1YQY 1ZXV 4DV8 4PKQ 4PKR 4PKT 4PKU 4PKV 4PKW
• Descriptor: Lethal factor, ZINC ION, N~2~-[(4-fluoro-3-methylphenyl)sulfonyl]-N-hydroxy-N~2~-(pyridin-3-ylmethyl)-D-alaninamide, ... (6 entities in total)
• Functional Keywords: anthrax toxin, lethal factor, metalloproteinase, metalloprotease, structural dynamics, ligand-induced conformational change, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Bacillus anthracis
• Total number of polymer chains: 1
• Total formula weight: 61085.08

Authors

Maize, K.M.,De la Mora, T.,Finzel, B.C. (deposition date: 2014-05-15, release date: 2014-11-12, Last modification date: 2023-12-27)

Primary citation

Maize, K.M.,Kurbanov, E.K.,De La Mora-Rey, T.,Geders, T.W.,Hwang, D.J.,Walters, M.A.,Johnson, R.L.,Amin, E.A.,Finzel, B.C.
Anthrax toxin lethal factor domain 3 is highly mobile and responsive to ligand binding.
Acta Crystallogr.,Sect.D, 70:2813-2822, 2014

PubMed Abstract: The secreted anthrax toxin consists of three components: the protective antigen (PA), edema factor (EF) and lethal factor (LF). LF, a zinc metalloproteinase, compromises the host immune system primarily by targeting mitogen-activated protein kinase kinases in macrophages. Peptide substrates and small-molecule inhibitors bind LF in the space between domains 3 and 4 of the hydrolase. Domain 3 is attached on a hinge to domain 2 via residues Ile300 and Pro385, and can move through an angular arc of greater than 35° in response to the binding of different ligands. Here, multiple LF structures including five new complexes with co-crystallized inhibitors are compared and three frequently populated LF conformational states termed `bioactive', `open' and `tight' are identified. The bioactive position is observed with large substrate peptides and leaves all peptide-recognition subsites open and accessible. The tight state is seen in unliganded and small-molecule complex structures. In this state, domain 3 is clamped over certain substrate subsites, blocking access. The open position appears to be an intermediate state between these extremes and is observed owing to steric constraints imposed by specific bound ligands. The tight conformation may be the lowest-energy conformation among the reported structures, as it is the position observed with no bound ligand, while the open and bioactive conformations are likely to be ligand-induced.

PubMed: 25372673
DOI: 10.1107/S1399004714018161

Experimental method

X-RAY DIFFRACTION (2.3 Å)