9P1B

P. putida mandelate racemase co-crystallized with tavaborole

This is a non-PDB format compatible entry.

Summary for 9P1B

• Entry DOI: 10.2210/pdb9p1b/pdb
• Descriptor: Mandelate racemase, Tavaborole, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: inhibitor, boronic acid, isomerase
• Biological source: Pseudomonas putida
• Total number of polymer chains: 2
• Total formula weight: 83272.05

Authors

Jabin, A.,Hayden, J.A.,Bearne, S.L.,St Maurice, M. (deposition date: 2025-06-09, release date: 2026-01-14, Last modification date: 2026-01-28)

Primary citation

Hayden, J.A.,Jabin, A.,Kuehm, O.P.,Moncrief, J.G.,St Maurice, M.,Bearne, S.L.
Inhibition of Mandelate Racemase by Boron-Based Inhibitors: Different Binding Modes for Benzoxaboroles Versus Boronic Acids.
Biochemistry, 65:222-235, 2026

PubMed Abstract: Mandelate racemase (MR) catalyzes the Mg-dependent interconversion of ()- and ()-mandelate and has been employed as a model enzyme to demonstrate that an enzyme catalyzing the deprotonation of a carbon acid substrate may be inhibited by boronic acids. We report a detailed structure-activity-based study of the ability of various boronic acid derivatives to competitively inhibit MR. 2-Naphthylboronic acid ( = 0.32 ± 0.01 μM), furan-3-boronic acid ( = 10 ± 1 μM), and thiophene-3-boronic acid ( = 1.27 ± 0.06 μM) were potent inhibitors of MR, while 1-naphthylboronic acid ( = 28 ± 3 μM) and nitrogen-heterocycles (.., isoxazole, indole, 1-indazole, pyridine, and pyrimidine) bearing boronic acid groups were generally weaker inhibitors. A chlorine substituent on the pyridine (.., 2-chloro-pyridine-5-boronic or 2-chloro-pyridine-4-boronic acids) or pyrimidine (.., 2-chloro-pyrimidine-5-boronic acid) ring enhanced the binding affinity by 3- to 27-fold. Surprisingly, benzoxaboroles, including the antifungal agent tavaborole (.., 5-fluorobenzoxaborole, = 1.06 ± 0.09 μM), were also potent competitive inhibitors of MR. The pH-dependence of the inhibition by benzoxaborole suggested that the species with the tetrahedral, sp-hybridized boron atom was the more potent inhibitor. Interestingly, B NMR spectroscopy and X-ray crystallography revealed that aryl boronic acids and benzoxaboroles interact with MR via different binding modes. Unlike phenylboronic acid, which forms an N-B bond with His 297 at the active site, the 1.8-Å resolution structure of the MR-tavaborole adduct revealed the presence of an N-B bond between the bound tavaborole and Lys 166 at the active site.

PubMed: 41467460
DOI: 10.1021/acs.biochem.5c00655

Experimental method

X-RAY DIFFRACTION (1.8 Å)