5MSR

Structure of the unmodified PCP-R domain of carboxylic acid reductase (CAR) from Segniliparus rugosus in complex with NADPH, P43 form

Summary for 5MSR

• Entry DOI: 10.2210/pdb5msr/pdb
• Descriptor: Thioester reductase domain-containing protein, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE (3 entities in total)
• Functional Keywords: adenylation domain, carboxylic acid reductase, oxidoreductase
• Biological source: Segniliparus rugosus
• Total number of polymer chains: 4
• Total formula weight: 516446.28

Authors

Gahloth, D.,Leys, D. (deposition date: 2017-01-05, release date: 2017-07-05, Last modification date: 2024-01-17)

Primary citation

Gahloth, D.,Dunstan, M.S.,Quaglia, D.,Klumbys, E.,Lockhart-Cairns, M.P.,Hill, A.M.,Derrington, S.R.,Scrutton, N.S.,Turner, N.J.,Leys, D.
Structures of carboxylic acid reductase reveal domain dynamics underlying catalysis.
Nat. Chem. Biol., 13:975-981, 2017

PubMed Abstract: Carboxylic acid reductase (CAR) catalyzes the ATP- and NADPH-dependent reduction of carboxylic acids to the corresponding aldehydes. The enzyme is related to the nonribosomal peptide synthetases, consisting of an adenylation domain fused via a peptidyl carrier protein (PCP) to a reductase termination domain. Crystal structures of the CAR adenylation-PCP didomain demonstrate that large-scale domain motions occur between the adenylation and thiolation states. Crystal structures of the PCP-reductase didomain reveal that phosphopantetheine binding alters the orientation of a key Asp, resulting in a productive orientation of the bound nicotinamide. This ensures that further reduction of the aldehyde product does not occur. Combining crystallography with small-angle X-ray scattering (SAXS), we propose that molecular interactions between initiation and termination domains are limited to competing PCP docking sites. This theory is supported by the fact that (R)-pantetheine can support CAR activity for mixtures of the isolated domains. Our model suggests directions for further development of CAR as a biocatalyst.

PubMed: 28719588
DOI: 10.1038/nchembio.2434

Experimental method

X-RAY DIFFRACTION (2.37 Å)