6QFE

Crystal Structure of Human Kallikrein 5 in complex with GSK144


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.67 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.213 

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Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Evaluation of a crystallographic surrogate for kallikrein 5 in the discovery of novel inhibitors for Netherton syndrome.

Thorpe, J.H.Edgar, E.V.Smith, K.J.Lewell, X.Q.Rella, M.White, G.V.Polyakova, O.Nassau, P.Walker, A.L.Holmes, D.S.Pearce, A.C.Wang, Y.Liddle, J.Hovnanian, A.

(2019) Acta Crystallogr F Struct Biol Commun 75: 385-391

  • DOI: https://doi.org/10.1107/S2053230X19003169
  • Primary Citation of Related Structures:  
    6QFE, 6QFF, 6QFG, 6QFH

  • PubMed Abstract: 

    The inhibition of kallikrein 5 (KLK5) has been identified as a potential strategy for treatment of the genetic skin disorder Netherton syndrome, in which loss-of-function mutations in the SPINK5 gene lead to down-regulation of the endogenous inhibitor LEKTI-1 and profound skin-barrier defects with severe allergic manifestations. To aid in the development of a medicine for this target, an X-ray crystallographic system was developed to facilitate fragment-guided chemistry and knowledge-based drug-discovery approaches. Here, the development of a surrogate crystallographic system in place of KLK5, which proved to be challenging to crystallize, is described. The biochemical robustness of the crystallographic surrogate and the suitability of the system for the study of small nonpeptidic fragments and lead-like molecules are demonstrated.


  • Organizational Affiliation

    GlaxoSmithKline, Medicinal Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, England.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Kallikrein-5
A, B
227Homo sapiensMutation(s): 0 
Gene Names: KLK5SCTEUNQ570/PRO1132
EC: 3.4.21
UniProt & NIH Common Fund Data Resources
Find proteins for Q9Y337 (Homo sapiens)
Explore Q9Y337 
Go to UniProtKB:  Q9Y337
PHAROS:  Q9Y337
GTEx:  ENSG00000167754 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9Y337
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
C, D
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
J08 Binding MOAD:  6QFE IC50: 80 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.67 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.213 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 126.916α = 90
b = 83.84β = 116.23
c = 62.714γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
Aimlessdata scaling
PHASERphasing
BUSTERrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2019-05-08 
  • Deposition Author(s): Thorpe, J.H.

Revision History  (Full details and data files)

  • Version 1.0: 2019-05-08
    Type: Initial release
  • Version 1.1: 2019-05-15
    Changes: Data collection, Database references
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Structure summary
  • Version 2.1: 2024-01-24
    Changes: Data collection, Database references, Refinement description, Structure summary