4PQA

Crystal Structure of succinyl-diaminopimelate desuccinylase from Neisseria meningitidis MC58 in complex with the Inhibitor Captopril

Summary for 4PQA

• Entry DOI: 10.2210/pdb4pqa/pdb
• Descriptor: Succinyl-diaminopimelate desuccinylase, L-CAPTOPRIL, SULFATE ION, ... (5 entities in total)
• Functional Keywords: captopril, m20 aminopeptidase, dape, csgid, metaloenzyme, structural genomics, niaid, national institute of allergy and infectious diseases, center for structural genomics of infectious diseases, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Neisseria meningitidis
• Total number of polymer chains: 1
• Total formula weight: 41817.78

Authors

Nocek, B.,Starus, A.,Holz, R.,Anderson, W.F.,Joachimiak, A.,Center for Structural Genomics of Infectious Diseases (CSGID) (deposition date: 2014-03-01, release date: 2014-04-30, Last modification date: 2024-02-28)

Primary citation

Starus, A.,Nocek, B.,Bennett, B.,Larrabee, J.A.,Shaw, D.L.,Sae-Lee, W.,Russo, M.T.,Gillner, D.M.,Makowska-Grzyska, M.,Joachimiak, A.,Holz, R.C.
Inhibition of the dapE-Encoded N-Succinyl-L,L-diaminopimelic Acid Desuccinylase from Neisseria meningitidis by L-Captopril.
Biochemistry, 54:4834-4844, 2015

PubMed Abstract: Binding of the competitive inhibitor L-captopril to the dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase from Neisseria meningitidis (NmDapE) was examined by kinetic, spectroscopic, and crystallographic methods. L-Captopril, an angiotensin-converting enzyme (ACE) inhibitor, was previously shown to be a potent inhibitor of the DapE from Haemophilus influenzae (HiDapE) with an IC50 of 3.3 μM and a measured Ki of 1.8 μM and displayed a dose-responsive antibiotic activity toward Escherichia coli. L-Captopril is also a competitive inhibitor of NmDapE with a Ki of 2.8 μM. To examine the nature of the interaction of L-captopril with the dinuclear active site of DapE, we have obtained electron paramagnetic resonance (EPR) and magnetic circular dichroism (MCD) data for the enzymatically hyperactive Co(II)-substituted forms of both HiDapE and NmDapE. EPR and MCD data indicate that the two Co(II) ions in DapE are antiferromagnetically coupled, yielding an S = 0 ground state, and suggest a thiolate bridge between the two metal ions. Verification of a thiolate-bridged dinuclear complex was obtained by determining the three-dimensional X-ray crystal structure of NmDapE in complex with L-captopril at 1.8 Å resolution. Combination of these data provides new insights into binding of L-captopril to the active site of DapE enzymes as well as important inhibitor-active site residue interaction's. Such information is critical for the design of new, potent inhibitors of DapE enzymes.

PubMed: 26186504
DOI: 10.1021/acs.biochem.5b00475

Experimental method

X-RAY DIFFRACTION (1.78 Å)