5MIM

Xray structure of human furin bound with the 2,5-dideoxystreptamine derived small molecule inhibitor 1n


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.184 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.166 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structural Studies Revealed Active Site Distortions of Human Furin by a Small Molecule Inhibitor.

Dahms, S.O.Jiao, G.S.Than, M.E.

(2017) ACS Chem Biol 12: 1211-1216

  • DOI: https://doi.org/10.1021/acschembio.6b01110
  • Primary Citation of Related Structures:  
    5MIM

  • PubMed Abstract: 

    Proprotein convertases (PCs) represent highly selective serine proteases that activate their substrates upon proteolytic cleavage. Their inhibition is a promising strategy for the treatment of several pathologies including cancer, atherosclerosis, hypercholesterolaemia, and infectious diseases. Here, we present the first experimental complex of furin with a non-substrate-like small molecule inhibitor, and the X-ray structure of the enzyme complexed to the small molecule inhibitor 1 at 1.9 Å resolution. Two molecules of inhibitor 1 were found to interact with furin. One is anchored at the S4 pocket of the enzyme and interferes directly with the conformation and function of the catalytic triade; the other molecule shows weaker binding and interacts with a distant, less conserved region of furin. The observed binding modes represent a new inhibition strategy of furin and imply the possibility to attain specificity among the PCs providing an innovative starting point of structure guided inhibitor development for furin.


  • Organizational Affiliation

    Protein Crystallography Group, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) , Beutenbergstr. 11, 07745 Jena, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Furin482Homo sapiensMutation(s): 0 
Gene Names: FURINFURPACEPCSK3
EC: 3.4.21.75
UniProt & NIH Common Fund Data Resources
Find proteins for P09958 (Homo sapiens)
Explore P09958 
Go to UniProtKB:  P09958
PHAROS:  P09958
GTEx:  ENSG00000140564 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP09958
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1N
Query on 1N

Download Ideal Coordinates CCD File 
J [auth A],
K [auth A]
1-[(1~{R},2~{R},4~{S},5~{S})-2,4-bis(4-carbamimidamidophenoxy)-5-[(4-carbamimidamidophenyl)amino]cyclohexyl]guanidine
C28 H37 N13 O2
PKMXMBXOZUEHDV-UARRHKHWSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
B [auth A],
C [auth A],
D [auth A]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
I [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
NA
Query on NA

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
G [auth A],
H [auth A]
SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1N Binding MOAD:  5MIM Ki: 46 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.184 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.166 
  • Space Group: P 65 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 132.204α = 90
b = 132.204β = 90
c = 155.727γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XDSdata scaling
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-05-10
    Type: Initial release
  • Version 1.1: 2017-05-31
    Changes: Database references
  • Version 1.2: 2024-01-17
    Changes: Advisory, Data collection, Database references, Derived calculations, Refinement description