5VAN

Crystal Structure of Beta-Klotho


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.187 

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This is version 2.1 of the entry. See complete history


Literature

Structures of beta-klotho reveal a 'zip code'-like mechanism for endocrine FGF signalling.

Lee, S.Choi, J.Mohanty, J.Sousa, L.P.Tome, F.Pardon, E.Steyaert, J.Lemmon, M.A.Lax, I.Schlessinger, J.

(2018) Nature 553: 501-505

  • DOI: https://doi.org/10.1038/nature25010
  • Primary Citation of Related Structures:  
    5VAK, 5VAN, 5VAQ

  • PubMed Abstract: 

    Canonical fibroblast growth factors (FGFs) activate FGF receptors (FGFRs) through paracrine or autocrine mechanisms in a process that requires cooperation with heparan sulfate proteoglycans, which function as co-receptors for FGFR activation. By contrast, endocrine FGFs (FGF19, FGF21 and FGF23) are circulating hormones that regulate critical metabolic processes in a variety of tissues. FGF19 regulates bile acid synthesis and lipogenesis, whereas FGF21 stimulates insulin sensitivity, energy expenditure and weight loss. Endocrine FGFs signal through FGFRs in a manner that requires klothos, which are cell-surface proteins that possess tandem glycosidase domains. Here we describe the crystal structures of free and ligand-bound β-klotho extracellular regions that reveal the molecular mechanism that underlies the specificity of FGF21 towards β-klotho and demonstrate how the FGFR is activated in a klotho-dependent manner. β-Klotho serves as a primary 'zip code'-like receptor that acts as a targeting signal for FGF21, and FGFR functions as a catalytic subunit that mediates intracellular signalling. Our structures also show how the sugar-cutting enzyme glycosidase has evolved to become a specific receptor for hormones that regulate metabolic processes, including the lowering of blood sugar levels. Finally, we describe an agonistic variant of FGF21 with enhanced biological activity and present structural insights into the potential development of therapeutic agents for diseases linked to endocrine FGFs.


  • Organizational Affiliation

    Department of Pharmacology and Yale Cancer Biology Institute, Yale School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-klotho954Homo sapiensMutation(s): 2 
Gene Names: KLB
UniProt & NIH Common Fund Data Resources
Find proteins for Q86Z14 (Homo sapiens)
Explore Q86Z14 
Go to UniProtKB:  Q86Z14
PHAROS:  Q86Z14
GTEx:  ENSG00000134962 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ86Z14
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Nb914134Lama glamaMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

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Entity ID: 3
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
C
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAG
Query on NAG

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

Download Ideal Coordinates CCD File 
K [auth A]2-(N-MORPHOLINO)-ETHANESULFONIC ACID
C6 H13 N O4 S
SXGZJKUKBWWHRA-UHFFFAOYSA-N
BGC
Query on BGC

Download Ideal Coordinates CCD File 
I [auth A],
J [auth A]
beta-D-glucopyranose
C6 H12 O6
WQZGKKKJIJFFOK-VFUOTHLCSA-N
MAN
Query on MAN

Download Ideal Coordinates CCD File 
G [auth A],
H [auth A]
alpha-D-mannopyranose
C6 H12 O6
WQZGKKKJIJFFOK-PQMKYFCFSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.187 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.683α = 90
b = 144.069β = 90
c = 215.612γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data processing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-01-31
    Type: Initial release
  • Version 1.1: 2018-02-07
    Changes: Database references
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Atomic model, Data collection, Derived calculations, Structure summary
  • Version 2.1: 2021-03-24
    Changes: Source and taxonomy, Structure summary