4H2E

Crystal structure of an MMP twin inhibitor complexing two MMP-9 catalytic domains


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.311 
  • R-Value Work: 0.277 
  • R-Value Observed: 0.279 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Crystallization of bi-functional ligand protein complexes.

Antoni, C.Vera, L.Devel, L.Catalani, M.P.Czarny, B.Cassar-Lajeunesse, E.Nuti, E.Rossello, A.Dive, V.Stura, E.A.

(2013) J Struct Biol 182: 246-254

  • DOI: https://doi.org/10.1016/j.jsb.2013.03.015
  • Primary Citation of Related Structures:  
    4H1Q, 4H2E, 4H30, 4H3X, 4H49, 4H76, 4H82, 4H84, 4HMA, 4I03

  • PubMed Abstract: 

    Homodimerization is important in signal transduction and can play a crucial role in many other biological systems. To obtaining structural information for the design of molecules able to control the signalization pathways, the proteins involved will have to be crystallized in complex with ligands that induce dimerization. Bi-functional drugs have been generated by linking two ligands together chemically and the relative crystallizability of complexes with mono-functional and bi-functional ligands has been evaluated. There are problems associated with crystallization with such ligands, but overall, the advantages appear to be greater than the drawbacks. The study involves two matrix metalloproteinases, MMP-12 and MMP-9. Using flexible and rigid linkers we show that it is possible to control the crystal packing and that by changing the ligand-enzyme stoichiometric ratio, one can toggle between having one bi-functional ligand binding to two enzymes and having the same ligand bound to each enzyme. The nature of linker and its point of attachment on the ligand can be varied to aid crystallization, and such variations can also provide valuable structural information about the interactions made by the linker with the protein. We report here the crystallization and structure determination of seven ligand-dimerized complexes. These results suggest that the use of bi-functional drugs can be extended beyond the realm of protein dimerization to include all drug design projects.


  • Organizational Affiliation

    CEA, iBiTec-S, Service d'Ingénierie Moléculaire des Protéines-SIMOPRO, Gif-sur-Yvette F-91191, France. [email protected]


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Matrix metalloproteinase-9
A, B
164Homo 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 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0Y3
Query on 0Y3

Download Ideal Coordinates CCD File 
W [auth B]N,N'-bis(4-{[(3R)-3-[(biphenyl-4-ylsulfonyl)(propan-2-yloxy)amino]-4-(hydroxyamino)-4-oxobutyl]amino}-4-oxobutyl)benzene-1,3-dicarboxamide
C54 H66 N8 O14 S2
QTGQZAQZBAEHLR-URZIEALYSA-N
BCN
Query on BCN

Download Ideal Coordinates CCD File 
BA [auth B],
P [auth A],
Q [auth A]
BICINE
C6 H13 N O4
FSVCELGFZIQNCK-UHFFFAOYSA-N
PEG
Query on PEG

Download Ideal Coordinates CCD File 
G [auth A]
H [auth A]
I [auth A]
J [auth A]
K [auth A]
G [auth A],
H [auth A],
I [auth A],
J [auth A],
K [auth A],
L [auth A],
X [auth B],
Y [auth B],
Z [auth B]
DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
ZN
Query on ZN

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C [auth A],
D [auth A],
R [auth B],
S [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
ACT
Query on ACT

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AA [auth B],
M [auth A],
N [auth A],
O [auth A]
ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
CA
Query on CA

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
T [auth B],
U [auth B],
V [auth B]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
0Y3 BindingDB:  4H2E IC50: min: 8.3, max: 38 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.311 
  • R-Value Work: 0.277 
  • R-Value Observed: 0.279 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 40.18α = 90
b = 97.4β = 111.99
c = 45.69γ = 90
Software Package:
Software NamePurpose
DNAdata collection
MOLREPphasing
PHENIXrefinement
XDSdata reduction
XDSdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-04-24
    Type: Initial release
  • Version 1.1: 2013-05-01
    Changes: Database references
  • Version 1.2: 2014-10-08
    Changes: Structure summary
  • Version 1.3: 2015-08-12
    Changes: Database references
  • Version 1.4: 2017-05-31
    Changes: Structure summary
  • Version 1.5: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description