8XR4

Crystal structure of AKRtyl-NADP(H) complex

Summary for 8XR4

• Entry DOI: 10.2210/pdb8xr4/pdb
• Descriptor: Aldo/keto reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE (3 entities in total)
• Functional Keywords: oxidoreductase
• Biological source: Streptomyces xinghaiensis
• Total number of polymer chains: 8
• Total formula weight: 296296.86

Authors

Lin, S.,Dai, S.,Xiao, Z. (deposition date: 2024-01-06, release date: 2024-04-10, Last modification date: 2024-05-08)

Primary citation

Xiao, Z.,Zha, J.,Yang, X.,Huang, T.,Huang, S.,Liu, Q.,Wang, X.,Zhong, J.,Zheng, J.,Liang, R.,Deng, Z.,Zhang, J.,Lin, S.,Dai, S.
A three-level regulatory mechanism of the aldo-keto reductase subfamily AKR12D.
Nat Commun, 15:2128-2128, 2024

PubMed Abstract: Modulation of protein function through allosteric regulation is central in biology, but biomacromolecular systems involving multiple subunits and ligands may exhibit complex regulatory mechanisms at different levels, which remain poorly understood. Here, we discover an aldo-keto reductase termed AKRtyl and present its three-level regulatory mechanism. Specifically, by combining steady-state and transient kinetics, X-ray crystallography and molecular dynamics simulation, we demonstrate that AKRtyl exhibits a positive synergy mediated by an unusual Monod-Wyman-Changeux (MWC) paradigm of allosteric regulation at low concentrations of the cofactor NADPH, but an inhibitory effect at high concentrations is observed. While the substrate tylosin binds at a remote allosteric site with positive cooperativity. We further reveal that these regulatory mechanisms are conserved in AKR12D subfamily, and that substrate cooperativity is common in AKRs across three kingdoms of life. This work provides an intriguing example for understanding complex allosteric regulatory networks.

PubMed: 38459030
DOI: 10.1038/s41467-024-46363-z

Experimental method

X-RAY DIFFRACTION (1.94 Å)