5Y9L

Human kallikrein 7 in complex with 1,3,6-trisubstituted 1,4-diazepane-7-one

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 0.276 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.211 

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Literature

Discovery and structure-activity relationship study of 1,3,6-trisubstituted 1,4-diazepane-7-ones as novel human kallikrein 7 inhibitors

Murafuji, H., Sakai, H., Goto, M., Imajo, S., Sugawara, H., Muto, T.

(2017) Bioorg Med Chem Lett 27: 5272-5276

  • DOI: https://doi.org/10.1016/j.bmcl.2017.10.030
  • Primary Citation of Related Structures:  
    5Y9L, 5YJK

  • PubMed Abstract: 

    Compound 1, composed of a 1,3,6-trisubstituted 1,4-diazepane-7-one, was discovered as a novel human kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme, SCCE) inhibitor, and its derivatives were synthesized and evaluated. Structure-activity relationship studies of the amidoxime unit and benzoic acid part of this new scaffold led to the identification of 25 and 34, which were more potent than the hit compound, 1. The X-ray co-crystal structure of compound 25 and human KLK7 revealed the characteristic interactions and enabled explanations of the structure-activity relationship.

    • Organizational Affiliation: 

    Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan. Electronic address: murafuji.hidenobu.bc@asubio.co.jp.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Kallikrein-7224Homo sapiensMutation(s): 0 
Gene Names: KLK7, PRSS6, SCCE
EC: 3.4.21.117
UniProt & NIH Common Fund Data Resources
Find proteins for P49862 (Homo sapiens)
Explore P49862 
Go to UniProtKB:  P49862
PHAROS:  P49862
GTEx:  ENSG00000169035 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP49862
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
8R3
Query on 8R3
Download Ideal Coordinates CCD File 
B [auth A]3-[2-[(3Z,6R)-6-[(5-chloranyl-2-methoxy-phenyl)methyl]-3-(dimethylhydrazinylidene)-7-oxidanylidene-1,4-diazepan-1-yl]ethanoylamino]benzoic acid
C24 H28 Cl N5 O5
STRUTOBZXDUGAL-QGZVFWFLSA-N
CL
Query on CL
Download Ideal Coordinates CCD File 
C [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
8R3 Binding MOAD:  5Y9L IC50: 1900 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 0.276 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.211 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.895α = 90
b = 90.926β = 90
c = 92.03γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling
AMoREphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

  • Released Date: 2017-11-29 
    • Deposition Author(s): Sugawara, H.

Revision History  (Full details and data files)

  • Version 1.0: 2017-11-29
    Type: Initial release
  • Version 1.1: 2023-11-22
    Changes: Data collection, Database references, Derived calculations, Refinement description