8JWO

Crystal structure of AKRtyl-tylosin complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.25 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.183 

Starting Model: experimental
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Literature

A three-level regulatory mechanism of the aldo-keto reductase subfamily AKR12D.

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.

(2024) Nat Commun 15: 2128-2128

  • DOI: https://doi.org/10.1038/s41467-024-46363-z
  • Primary Citation of Related Structures:  
    8JWK, 8JWL, 8JWM, 8JWN, 8JWO, 8XR2, 8XR3, 8XR4

  • 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.


  • Organizational Affiliation

    State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory on Metabolic & Developmental Sciences, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Aldo/keto reductase
A, B, C, D, E
A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P
351Streptomyces xinghaiensisMutation(s): 0 
Gene Names: DC095_024450SFRA_012675
UniProt
Find proteins for A0A3R7J519 (Streptomyces xinghaiensis)
Explore A0A3R7J519 
Go to UniProtKB:  A0A3R7J519
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupA0A3R7J519
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
TYK (Subject of Investigation/LOI)
Query on TYK

Download Ideal Coordinates CCD File 
AA [auth K]
BA [auth L]
CA [auth M]
DA [auth N]
EA [auth O]
AA [auth K],
BA [auth L],
CA [auth M],
DA [auth N],
EA [auth O],
FA [auth P],
Q [auth A],
R [auth B],
S [auth C],
T [auth D],
U [auth E],
V [auth F],
W [auth G],
X [auth H],
Y [auth I],
Z [auth J]
TYLOSIN
C46 H77 N O17
WBPYTXDJUQJLPQ-VMXQISHHSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.25 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.183 
  • Space Group: P 43
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 111.021α = 90
b = 111.021β = 90
c = 560.041γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-3000data scaling
PDB_EXTRACTdata extraction
HKL-3000data reduction
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Natural Science Foundation of China (NSFC)China21632007

Revision History  (Full details and data files)

  • Version 1.0: 2024-04-10
    Type: Initial release