The molecular basis of Human FN3K mediated phosphorylation of glycated substrates

Garg, Ankur, On, Kin Fan, Xiao, Yang, Elkayam, Elad, Cifani, Paolo, David, Yael, Joshua-Tor, Leemor (January 2025) The molecular basis of Human FN3K mediated phosphorylation of glycated substrates. Nature Communications, 16 (1). p. 941. ISSN 2041-1723 (Public Dataset)

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Abstract

Glycation, a non-enzymatic post-translational modification occurring on proteins, can be actively reversed via site-specific phosphorylation of the fructose-lysine moiety by FN3K kinase, to impact the cellular function of the target protein. A regulatory axis between FN3K and glycated protein targets has been associated with conditions like diabetes and cancer. However, the molecular basis of this relationship has not been explored so far. Here, we determined a series of crystal structures of HsFN3K in the apo-state, and in complex with different nucleotide analogs together with a sugar substrate mimic to reveal the features important for its kinase activity and substrate recognition. Additionally, the dynamics in sugar substrate binding during the kinase catalytic cycle provide important mechanistic insights into HsFN3K function. Our structural work provides the molecular basis for rational small molecule design targeting FN3K.

Item Type: Paper
Subjects: Investigative techniques and equipment
organism description > animal
organism description > animal > mammal > primates > hominids
organism description > animal > mammal > primates > hominids > human
organism description > animal > mammal
organism description > animal > mammal > primates
Investigative techniques and equipment > x ray crystallography
CSHL Authors:
Communities: CSHL Cancer Center Program > Gene Regulation and Inheritance Program
CSHL labs > Joshua-Tor lab
CSHL Cancer Center Program
CSHL labs > Cifani lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 22 January 2025
Date Deposited: 23 Jan 2025 15:04
Last Modified: 23 Jan 2025 15:04
Related URLs:
Dataset ID:
  • Protein Data Bank: 9CX8
  • Protein Data Bank: 9CXV
  • Protein Data Bank: 9CXW
  • Protein Data Bank: 9CXM
  • Protein Data Bank: 9CXN
  • Protein Data Bank: 9CXO
URI: https://repository.cshl.edu/id/eprint/41777

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