1HV5

CRYSTAL STRUCTURE OF THE STROMELYSIN-3 (MMP-11) CATALYTIC DOMAIN COMPLEXED WITH A PHOSPHINIC INHIBITOR


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.262 
  • R-Value Work: 0.218 
  • R-Value Observed: 0.218 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Crystal structure of the stromelysin-3 (MMP-11) catalytic domain complexed with a phosphinic inhibitor mimicking the transition-state.

Gall, A.L.Ruff, M.Kannan, R.Cuniasse, P.Yiotakis, A.Dive, V.Rio, M.C.Basset, P.Moras, D.

(2001) J Mol Biol 307: 577-586

  • DOI: https://doi.org/10.1006/jmbi.2001.4493
  • Primary Citation of Related Structures:  
    1HV5

  • PubMed Abstract: 

    Stromelysin-3 (ST3) is a matrix metalloproteinase (MMP-11) whose proteolytic activity plays an important role in tumorigenicity enhancement. In breast cancer, ST3 is a bad prognosis marker: its expression is associated with a poor clinical outcome. This enzyme therefore represents an attractive therapeutic target. The topology of matrix metalloproteinases (MMPs) is remarkably well conserved, making the design of highly specific inhibitors difficult. The major difference between MMPs lies in the S(1)' subsite, a well-defined hydrophobic pocket of variable depth. The present crystal structure, the first 3D-structure of the ST3 catalytic domain in interaction with a phosphinic inhibitor mimicking a (d, l) peptide, clearly demonstrates that its S(1)' pocket corresponds to a tunnel running through the enzyme. This open channel is filled by the inhibitor P(1)' group which adopts a constrained conformation to fit this pocket, together with two water molecules interacting with the ST3-specific residue Gln215. These observations provide clues for the design of more specific inhibitors and show how ST3 can accommodate a phosphinic inhibitor mimicking a (d, l) peptide. The presence of a water molecule interacting with one oxygen atom of the inhibitor phosphinyl group and the proline residue of the Met-turn suggests how the intermediate formed during proteolysis may be stabilized. Furthermore, the hydrogen bond distance observed between the methyl of the phosphinic group and the carbonyl group of Ala182 mimics the interaction between this carbonyl group and the amide group of the cleaved peptidic bond. Our crystal structure provides a good model to study the MMPs mechanism of proteolysis.


  • Organizational Affiliation

    Structural Biology and Genomics Laboratory, I.G.B.M.C., B.P. 163, F67404, Illkirch Cedex, France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
STROMELYSIN 3
A, B, C, D, E
A, B, C, D, E, F
165Mus musculusMutation(s): 0 
Gene Names: STRO3 (101-264)
EC: 3.4.24
UniProt & NIH Common Fund Data Resources
Find proteins for Q02853 (Mus musculus)
Explore Q02853 
Go to UniProtKB:  Q02853
IMPC:  MGI:97008
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ02853
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
RXP
Query on RXP

Download Ideal Coordinates CCD File 
DA [auth D]
JA [auth E]
L [auth A]
PA [auth F]
R [auth B]
DA [auth D],
JA [auth E],
L [auth A],
PA [auth F],
R [auth B],
X [auth C]
1-BENZYLOXYCARBONYLAMINO-2-PHENYL-ETHYL)-{2-[1-CARBAMOYL-2-(1H-INDOL-3-YL)-ETHYLCARBAMOYL]-5-PHENYL-PENTYL}-PHOSPHINIC ACID
C39 H43 N4 O6 P
YQEMFOGNUTYMTJ-JNBVYXHXSA-N
CPS
Query on CPS

Download Ideal Coordinates CCD File 
BA [auth D]
CA [auth D]
HA [auth E]
IA [auth E]
J [auth A]
BA [auth D],
CA [auth D],
HA [auth E],
IA [auth E],
J [auth A],
K [auth A],
NA [auth F],
OA [auth F],
P [auth B],
Q [auth B],
V [auth C],
W [auth C]
3-[(3-CHOLAMIDOPROPYL)DIMETHYLAMMONIO]-1-PROPANESULFONATE
C32 H58 N2 O7 S
UMCMPZBLKLEWAF-BCTGSCMUSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
EA [auth E]
FA [auth E]
G [auth A]
H [auth A]
KA [auth F]
EA [auth E],
FA [auth E],
G [auth A],
H [auth A],
KA [auth F],
LA [auth F],
M [auth B],
N [auth B],
S [auth C],
T [auth C],
Y [auth D],
Z [auth D]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
AA [auth D]
GA [auth E]
I [auth A]
MA [auth F]
O [auth B]
AA [auth D],
GA [auth E],
I [auth A],
MA [auth F],
O [auth B],
U [auth C]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
RXP BindingDB:  1HV5 Ki: min: 5, max: 5 (nM) from 2 assay(s)
PDBBind:  1HV5 Ki: 5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.262 
  • R-Value Work: 0.218 
  • R-Value Observed: 0.218 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 140.1α = 90
b = 148.5β = 90
c = 91.4γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
XDSdata reduction
AMoREphasing
CNSrefinement
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: 2001-03-28
    Type: Initial release
  • Version 1.1: 2008-04-27
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2024-02-07
    Changes: Data collection, Database references, Derived calculations