5I43

Crystal structure of the catalytic domain of MMP-12 in complex with a selective sugar-conjugated triazole-linked carboxylate chelator water-soluble inhibitor (DC32).

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.233 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.202 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history. 


Literature

Sugar-Based Arylsulfonamide Carboxylates as Selective and Water-Soluble Matrix Metalloproteinase-12 Inhibitors.

Nuti, E., Cuffaro, D., D'Andrea, F., Rosalia, L., Tepshi, L., Fabbi, M., Carbotti, G., Ferrini, S., Santamaria, S., Camodeca, C., Ciccone, L., Orlandini, E., Nencetti, S., Stura, E.A., Dive, V., Rossello, A.

(2016) ChemMedChem 11: 1626-1637

  • DOI: https://doi.org/10.1002/cmdc.201600235
  • Primary Citation of Related Structures:  
    5I0L, 5I12, 5I2Z, 5I3M, 5I43, 5I4O

  • PubMed Abstract: 

    Matrix metalloproteinase-12 (MMP-12) can be considered an attractive target to study selective inhibitors useful in the development of new therapies for lung and cardiovascular diseases. In this study, a new series of arylsulfonamide carboxylates, with increased hydrophilicity resulting from conjugation with a β-N-acetyl-d-glucosamine moiety, were designed and synthesized as MMP-12 selective inhibitors. Their inhibitory activity was evaluated on human MMPs by using the fluorimetric assay, and a crystallographic analysis was performed to characterize their binding mode. Among these glycoconjugates, a nanomolar MMP-12 inhibitor with improved water solubility, compound 3 [(R)-2-(N-(2-(3-(2-acetamido-2-deoxy-β-d-glucopyranosyl)thioureido)ethyl)biphenyl-4-ylsulfonamido)-3-methylbutanoic acid], was identified.

    • Organizational Affiliation: 

    Department of Pharmacy, University of Pisa, via Bonanno 6, 56126, Pisa, Italy.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Macrophage metalloelastase
A, B, C, D
159Homo sapiensMutation(s): 2 
Gene Names: MMP12, HME
EC: 3.4.24.65
UniProt & NIH Common Fund Data Resources
Find proteins for P39900 (Homo sapiens)
Explore P39900 
Go to UniProtKB:  P39900
PHAROS:  P39900
GTEx:  ENSG00000262406 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP39900
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
67M
Query on 67M
Download Ideal Coordinates CCD File 
HA [auth C],
J [auth A],
U [auth B],
UA [auth D]		(2R)-2-[({1-[3-({(2R,3R,4R,5S,6R)-3-(acetylamino)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)propyl]-1H-1,2,3-triazol-4-yl}methyl)(biphenyl-4-ylsulfonyl)amino]-3-methylbutanoic acid (non-preferred name)
C37 H47 N5 O13 S
GRIPTHDAFNBNAB-HTJFLOPLSA-N
DMS
Query on DMS
Download Ideal Coordinates CCD File 
FA [auth B],
PA [auth C]		DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
PGO
Query on PGO
Download Ideal Coordinates CCD File 
GA [auth B]
GB [auth D]
QA [auth C]
RA [auth C]
SA [auth C]
GA [auth B],
GB [auth D],
QA [auth C],
RA [auth C],
SA [auth C],
TA [auth C]
S-1,2-PROPANEDIOL
C3 H8 O2
DNIAPMSPPWPWGF-VKHMYHEASA-N
ZN
Query on ZN
Download Ideal Coordinates CCD File 
E [auth A]
F [auth A]
IA [auth C]
JA [auth C]
V [auth B]
E [auth A],
F [auth A],
IA [auth C],
JA [auth C],
V [auth B],
VA [auth D],
W [auth B],
WA [auth D]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
EDO
Query on EDO
Download Ideal Coordinates CCD File 
AA [auth B]
AB [auth D]
BA [auth B]
BB [auth D]
CA [auth B]
AA [auth B],
AB [auth D],
BA [auth B],
BB [auth D],
CA [auth B],
CB [auth D],
DA [auth B],
DB [auth D],
EA [auth B],
EB [auth D],
FB [auth D],
K [auth A],
L [auth A],
M [auth A],
N [auth A],
NA [auth C],
O [auth A],
OA [auth C],
P [auth A],
Q [auth A],
R [auth A],
S [auth A],
T [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
CA
Query on CA
Download Ideal Coordinates CCD File 
G [auth A]
H [auth A]
I [auth A]
KA [auth C]
LA [auth C]
G [auth A],
H [auth A],
I [auth A],
KA [auth C],
LA [auth C],
MA [auth C],
X [auth B],
XA [auth D],
Y [auth B],
YA [auth D],
Z [auth B],
ZA [auth D]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.233 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.202 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 64.03α = 90
b = 63.66β = 103.03
c = 79.03γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
Cootmodel building

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-07-06
    Type: Initial release
  • Version 1.1: 2016-07-13
    Changes: Database references
  • Version 1.2: 2016-08-17
    Changes: Database references
  • Version 1.3: 2018-01-24
    Changes: Source and taxonomy
  • Version 1.4: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Refinement description