Abstract
The Lon proteases are a unique family of chambered proteases with a built-in AAA+ (ATPases associated with diverse cellular activities) module. Here, crystal structures of a unique member of the Lon family with no intrinsic ATPase activity in the proteolytically active form are reported both alone and in complexes with three covalent inhibitors: two peptidomimetics and one derived from a natural product. This work reveals the unique architectural features of an ATP-independent Lon that selectively degrades unfolded protein substrates. Importantly, these results provide mechanistic insights into the recognition of inhibitors and polypeptide substrates within the conserved proteolytic chamber, which may aid the development of specific Lon-protease inhibitors.
Keywords:
Lon proteases; LonC; inhibitors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / metabolism*
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Amino Acid Sequence
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Bacterial Proteins / chemistry
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Bacterial Proteins / metabolism
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Boronic Acids / chemistry
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Boronic Acids / metabolism
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Bortezomib
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Catalytic Domain
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Crystallography, X-Ray
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Deinococcus / enzymology
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Lactones / chemistry
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Lactones / metabolism
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Models, Molecular
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Molecular Sequence Data
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Protease Inhibitors / chemistry*
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Protease Inhibitors / metabolism
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Protease La / antagonists & inhibitors*
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Protease La / chemistry*
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Protease La / metabolism
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Protein Conformation
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Pyrazines / chemistry
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Pyrazines / metabolism
Substances
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Bacterial Proteins
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Boronic Acids
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Lactones
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Protease Inhibitors
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Pyrazines
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omuralide
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Bortezomib
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Adenosine Triphosphate
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Protease La
Associated data
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PDB/4FW9
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PDB/4FWD
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PDB/4FWG
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PDB/4FWH