6S22

Crystal structure of the TgGalNAc-T3 in complex with UDP, manganese and FGF23c


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.96 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.180 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Molecular basis for fibroblast growth factor 23 O-glycosylation by GalNAc-T3.

de Las Rivas, M.Paul Daniel, E.J.Narimatsu, Y.Companon, I.Kato, K.Hermosilla, P.Thureau, A.Ceballos-Laita, L.Coelho, H.Bernado, P.Marcelo, F.Hansen, L.Maeda, R.Lostao, A.Corzana, F.Clausen, H.Gerken, T.A.Hurtado-Guerrero, R.

(2020) Nat Chem Biol 16: 351-360

  • DOI: https://doi.org/10.1038/s41589-019-0444-x
  • Primary Citation of Related Structures:  
    6S22, 6S24

  • PubMed Abstract: 

    Polypeptide GalNAc-transferase T3 (GalNAc-T3) regulates fibroblast growth factor 23 (FGF23) by O-glycosylating Thr178 in a furin proprotein processing motif RHT 178 R↓S. FGF23 regulates phosphate homeostasis and deficiency in GALNT3 or FGF23 results in hyperphosphatemia and familial tumoral calcinosis. We explored the molecular mechanism for GalNAc-T3 glycosylation of FGF23 using engineered cell models and biophysical studies including kinetics, molecular dynamics and X-ray crystallography of GalNAc-T3 complexed to glycopeptide substrates. GalNAc-T3 uses a lectin domain mediated mechanism to glycosylate Thr178 requiring previous glycosylation at Thr171. Notably, Thr178 is a poor substrate site with limiting glycosylation due to substrate clashes leading to destabilization of the catalytic domain flexible loop. We suggest GalNAc-T3 specificity for FGF23 and its ability to control circulating levels of intact FGF23 is achieved by FGF23 being a poor substrate. GalNAc-T3's structure further reveals the molecular bases for reported disease-causing mutations. Our findings provide an insight into how GalNAc-T isoenzymes achieve isoenzyme-specific nonredundant functions.


  • Organizational Affiliation

    BIFI, University of Zaragoza, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D, Zaragoza, Spain.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Polypeptide N-acetylgalactosaminyltransferase631Taeniopygia guttataMutation(s): 0 
Gene Names: GALNT3
EC: 2.4.1 (PDB Primary Data), 2.4.1.41 (UniProt)
UniProt
Find proteins for H0ZAB5 (Taeniopygia guttata)
Explore H0ZAB5 
Go to UniProtKB:  H0ZAB5
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupH0ZAB5
Glycosylation
Glycosylation Sites: 1
Sequence Annotations
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  • Reference Sequence

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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Fibroblast growth factor 23B [auth F]12Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q9GZV9 (Homo sapiens)
Explore Q9GZV9 
Go to UniProtKB:  Q9GZV9
PHAROS:  Q9GZV9
GTEx:  ENSG00000118972 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9GZV9
Glycosylation
Glycosylation Sites: 1Go to GlyGen: Q9GZV9-1
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 7 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
UDP
Query on UDP

Download Ideal Coordinates CCD File 
R [auth A]URIDINE-5'-DIPHOSPHATE
C9 H14 N2 O12 P2
XCCTYIAWTASOJW-XVFCMESISA-N
NGA (Subject of Investigation/LOI)
Query on NGA

Download Ideal Coordinates CCD File 
V [auth F]2-acetamido-2-deoxy-beta-D-galactopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-JAJWTYFOSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
T [auth A]2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
Q [auth A]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

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U [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
C [auth A]
D [auth A]
E [auth A]
F [auth A]
G [auth A]
C [auth A],
D [auth A],
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
K [auth A],
L [auth A],
M [auth A],
N [auth A],
O [auth A],
P [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
MN
Query on MN

Download Ideal Coordinates CCD File 
S [auth A]MANGANESE (II) ION
Mn
WAEMQWOKJMHJLA-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.96 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.180 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 50.957α = 90
b = 104.823β = 90
c = 143.466γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2019-12-25
    Type: Initial release
  • Version 1.1: 2020-01-22
    Changes: Database references
  • Version 1.2: 2020-03-04
    Changes: Data collection, Database references
  • Version 1.3: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Data collection, Derived calculations, Structure summary
  • Version 1.4: 2024-01-24
    Changes: Data collection, Database references, Refinement description, Structure summary
  • Version 1.5: 2024-11-06
    Changes: Structure summary