6QFG

Crystal Structure of Human Kallikrein 6 (I218Y) in complex with GSK144


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.68 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.193 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 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-6
A, B
223Homo sapiensMutation(s): 4 
Gene Names: KLK6PRSS18PRSS9
EC: 3.4.21
UniProt & NIH Common Fund Data Resources
Find proteins for Q92876 (Homo sapiens)
Explore Q92876 
Go to UniProtKB:  Q92876
PHAROS:  Q92876
GTEx:  ENSG00000167755 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ92876
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
J08 Binding MOAD:  6QFG IC50: 3010 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.68 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.193 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.4α = 90
b = 45.9β = 93.64
c = 89.35γ = 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 1.2: 2024-01-24
    Changes: Data collection, Database references, Refinement description