5F1V: biomimetic design results in a potent allosteric inhibitor of dihydrodipicolinate synthase from Campylobacter jejuni

Dihydrodipicolinate synthase (DHDPS), an enzyme required for bacterial peptidoglycan biosynthesis, catalyzes the condensation of pyruvate and beta-aspartate semialdehyde (ASA) to form a cyclic product which dehydrates to form dihydrodipicolinate. DHDPS has, for several years, been considered a putative target for novel antibiotics. We have designed the first potent inhibitor of this enzyme by mimicking its natural allosteric regulation by lysine, and obtained a crystal structure of the protein-inhibitor complex at 2.2 A resolution. This novel inhibitor, which we named "bislysine", resembles two lysine molecules linked by an ethylene bridge between the alpha-carbon atoms. Bislysine is a mixed partial inhibitor with respect to the first substrate, pyruvate, and a noncompetitive partial inhibitor with respect to ASA, and binds to all forms of the enzyme with a Ki near 200 nM, more than 300 times more tightly than lysine. Hill plots show that the inhibition is cooperative, indicating that the allosteric sites are not independent despite being located on opposite sides of the protein tetramer, separated by approximately 50 A. A mutant enzyme resistant to lysine inhibition, Y110F, is strongly inhibited by this novel inhibitor, suggesting this may be a promising strategy for antibiotic development.
PDB ID: 5F1VDownload
MMDB ID: 136606
PDB Deposition Date: 2015/11/30
Updated in MMDB: 2017/10
Experimental Method:
x-ray diffraction
Resolution: 2.2  Å
Source Organism:
Similar Structures:
Biological Unit for 5F1V: tetrameric; determined by author and by software (PISA)
Molecular Components in 5F1V
Label Count Molecule
Proteins (4 molecules)
4-hydroxy-tetrahydrodipicolinate Synthase(Gene symbol: dapA)
Molecule annotation
Chemicals (17 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB