4WZV

Crystal structure of a hydroxamate based inhibitor EN140 in complex with the MMP-9 catalytic domain


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.65 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.179 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

N-O-Isopropyl Sulfonamido-Based Hydroxamates as Matrix Metalloproteinase Inhibitors: Hit Selection and in Vivo Antiangiogenic Activity.

Nuti, E.Cantelmo, A.R.Gallo, C.Bruno, A.Bassani, B.Camodeca, C.Tuccinardi, T.Vera, L.Orlandini, E.Nencetti, S.Stura, E.A.Martinelli, A.Dive, V.Albini, A.Rossello, A.

(2015) J Med Chem 58: 7224-7240

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b00367
  • Primary Citation of Related Structures:  
    4WZV, 4XCT

  • PubMed Abstract: 

    Matrix metalloproteinases (MMPs) have been shown to be involved in tumor-induced angiogenesis. In particular, MMP-2, MMP-9, and MMP-14 have been reported to be crucial for tumor angiogenesis and the formation of metastasis, thus becoming attractive targets in cancer therapy. Here, we report our optimization effort to identify novel N-isopropoxy-arylsulfonamide hydroxamates with improved inhibitory activity toward MMP-2, MMP-9, and MMP-14 with respect to the previously discovered compound 1. A new series of hydroxamates was designed, synthesized, and tested for their antiangiogenic activity using in vitro assays with human umbilical vein endothelial cells (HUVECs). A nanomolar MMP-2, MMP-9, and MMP-14 inhibitor was identified, compound 3, able to potently inhibit angiogenesis in vitro and also in vivo in the matrigel sponge assay in mice. Finally, X-ray crystallographic and docking studies were conducted for compound 3 in order to investigate its binding mode to MMP-9 and MMP-14.


  • Organizational Affiliation

    Dipartimento di Farmacia, Università di Pisa , via Bonanno 6, 56126 Pisa, Italy.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Matrix metalloproteinase-9,Matrix metalloproteinase-9
A, B
160Homo sapiensMutation(s): 0 
Gene Names: MMP9CLG4B
EC: 3.4.24.35
UniProt & NIH Common Fund Data Resources
Find proteins for P14780 (Homo sapiens)
Explore P14780 
Go to UniProtKB:  P14780
PHAROS:  P14780
GTEx:  ENSG00000100985 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP14780
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 9 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
E40
Query on E40

Download Ideal Coordinates CCD File 
C [auth A],
N [auth B]
(2R)-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-hydroxy-2-{[(4'-methoxybiphenyl-4-yl)sulfonyl](propan-2-yloxy)amino}butanamide
C28 H29 N3 O8 S
WQCXDERWRJMJQA-RUZDIDTESA-N
PEG
Query on PEG

Download Ideal Coordinates CCD File 
DA [auth B],
EA [auth B],
L [auth A],
M [auth A]
DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
GOL
Query on GOL

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CA [auth B]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
PGO
Query on PGO

Download Ideal Coordinates CCD File 
J [auth A],
K [auth A]
S-1,2-PROPANEDIOL
C3 H8 O2
DNIAPMSPPWPWGF-VKHMYHEASA-N
ZN
Query on ZN

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D [auth A],
E [auth A],
O [auth B],
P [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
EDO
Query on EDO

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I [auth A],
T [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
AZI
Query on AZI

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U [auth B]AZIDE ION
N3
IVRMZWNICZWHMI-UHFFFAOYSA-N
CA
Query on CA

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F [auth A]
G [auth A]
H [auth A]
Q [auth B]
R [auth B]
F [auth A],
G [auth A],
H [auth A],
Q [auth B],
R [auth B],
S [auth B]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
NA
Query on NA

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AA [auth B]
BA [auth B]
V [auth B]
W [auth B]
X [auth B]
AA [auth B],
BA [auth B],
V [auth B],
W [auth B],
X [auth B],
Y [auth B],
Z [auth B]
SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.65 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.179 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 39.95α = 90
b = 97.39β = 112.72
c = 45.67γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XSCALEdata scaling
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-08-26
    Type: Initial release
  • Version 1.1: 2015-10-07
    Changes: Database references
  • Version 1.2: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Refinement description