PDBsum entry 5f1v

Lyase/lyase inhibitor

PDB id: 5f1v

Contents

Protein chains

296 a.a.

Ligands

3VN ×4

PGE ×3

EDO ×9

GOL

Waters ×401

PDB id:

5f1v

Name:

Lyase/lyase inhibitor

Title:

Biomimetic design results in a potent allosteric inhibitor of dihydrodipicolinate synthase from campylobacter jejuni

Structure:

4-hydroxy-tetrahydrodipicolinate synthase. Chain: a, b, c, d. Synonym: htpa synthase. Engineered: yes

Source:

Campylobacter jejuni. Organism_taxid: 197. Gene: dapa. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.20Å R-factor: 0.159 R-free: 0.203

Authors:

C.J.T.Conly,D.R.J.Palmer,D.A.R.Sanders

Key ref:

Y.V.Skovpen et al. (2016). Biomimetic Design Results in a Potent Allosteric Inhibitor of Dihydrodipicolinate Synthase from Campylobacter jejuni. J Am Chem Soc, 138, 2014-2020. PubMed id: 26836694 DOI: 10.1021/jacs.5b12695

Date:

30-Nov-15 Release date: 17-Feb-16

Protein chains

Q9PPB4  (DAPA_CAMJE) -  4-hydroxy-tetrahydrodipicolinate synthase from Campylobacter jejuni subsp. jejuni serotype O:2 (strain ATCC 700819 / NCTC 11168)

Seq: 298 a.a.

Struc: 296 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.4.3.3.7 - 4-hydroxy-tetrahydrodipicolinate synthase.
• Reaction: L-aspartate 4-semialdehyde + pyruvate = (2S,4S)-4-hydroxy-2,3,4,5- tetrahydrodipicolinate + H2O + H⁺

L-aspartate 4-semialdehyde + pyruvate (Bound ligand (Het Group name = GOL) matches with 71.43% similarity) = (2S,4S)-4-hydroxy-2,3,4,5- tetrahydrodipicolinate + H2O + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1021/jacs.5b12695

J Am Chem Soc 138:2014-2020 (2016)

PubMed id: 26836694

Biomimetic Design Results in a Potent Allosteric Inhibitor of Dihydrodipicolinate Synthase from Campylobacter jejuni.

Y.V.Skovpen, C.J.Conly, D.A.Sanders, D.R.Palmer.

ABSTRACT

Dihydrodipicolinate synthase (DHDPS), an enzyme required for bacterial peptidoglycan biosynthesis, catalyzes the condensation of pyruvate and β-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 Å resolution. This novel inhibitor, which we named "bislysine", resembles two lysine molecules linked by an ethylene bridge between the α-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 Å. 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.