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PDBsum entry 1jk3
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* Residue conservation analysis
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Enzyme class:
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E.C.3.4.24.65
- macrophage elastase.
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Reaction:
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Hydrolysis of soluble and insoluble elastin. Specific cleavages are also produced at 14-Ala-|-Leu-15 and 16-Tyr-|-Leu-17 in the B chain of insulin.
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Cofactor:
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Ca(2+); Zn(2+)
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DOI no:
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J Mol Biol
312:731-742
(2001)
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PubMed id:
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Substrate specificity determinants of human macrophage elastase (MMP-12) based on the 1.1 A crystal structure.
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R.Lang,
A.Kocourek,
M.Braun,
H.Tschesche,
R.Huber,
W.Bode,
K.Maskos.
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ABSTRACT
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The macrophage elastase enzyme (MMP-12) expressed mainly in alveolar macrophages
has been identified in the mouse lung as the main destructive agent associated
with cigarette smoking, which gives rise to emphysema, both directly via elastin
degradation and indirectly by disturbing the proteinase/antiproteinase balance
via inactivation of the alpha1-proteinase inhibitor (alpha1-PI), the antagonist
of the leukocyte elastase. The catalytic domain of human recombinant MMP-12 has
been crystallized in complex with the broad-specificity inhibitor batimastat
(BB-94). The crystal structure analysis of this complex, determined using X-ray
data to 1.1 A and refined to an R-value of 0.165, reveals an overall fold
similar to that of other MMPs. However, the S-shaped double loop connecting
strands III and IV is fixed closer to the beta-sheet and projects its His172
side-chain further into the rather hydrophobic active-site cleft, defining the
S3 and the S1-pockets and separating them from each other to a larger extent
than is observed in other MMPs. The S2-site is planar, while the characteristic
S1'-subsite is a continuous tube rather than a pocket, in which the
MMP-12-specific Thr215 replaces a Val residue otherwise highly conserved in
almost all other MMPs. This alteration might allow MMP-12 to accept P1' Arg
residues, making it unique among MMPs. The active-site cleft of MMP-12 is well
equipped to bind and efficiently cleave the AlaMetPhe-LeuGluAla sequence in the
reactive-site loop of alpha1-PI, as occurs experimentally. Similarities in
contouring and particularly a common surface hydrophobicity both inside and
distant from the active-site cleft explain why MMP-12 shares many substrates
with matrilysin (MMP-7). The MMP-12 structure is an excellent template for the
structure-based design of specific inhibitors for emphysema therapy and for the
construction of mutants to clarify the role of this MMP.
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Selected figure(s)
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Figure 1.
Figure 1. Ribbon plot of cdMMP-12 (yellow) displayed in
standard orientation. The cdMMP-12 ribbon shown together with
the bound batimastat inhibitor in the normal conformation, is
superimposed with the catalytic domains of MMP-1 (red, PDB
accession code 966C), MMP-2 (dark blue, lacking the fibronectin
type II domains for clarity, 1QIB), MMP-3 (green, 1CAQ), MMP-7
(dark orange, 1MMQ), MMP-8 (gray, 1MMB), MMP-12 (yellow), MMP-13
(light blue, 830C) and MMP-14 (violet red, 1BQQ). The catalytic
and the structural zinc ion and the three bound calcium ions are
displayed as pink and blue spheres, respectively, and the three
His residues liganding the catalytic zinc and the characteristic
Met236 are shown with all non-hydrogen atoms. The Figure was
made with BOBSCRIPT[55] and Raster3D. [56]
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Figure 4.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2001,
312,
731-742)
copyright 2001.
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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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Y.H.Xu,
L.Jia,
B.Quinn,
M.Zamzow,
K.Stringer,
B.Aronow,
Y.Sun,
W.Zhang,
K.D.Setchell,
and
G.A.Grabowski
(2011).
Global gene expression profile progression in Gaucher disease mouse models.
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BMC Genomics,
12,
20.
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A.Heinz,
M.C.Jung,
L.Duca,
W.Sippl,
S.Taddese,
C.Ihling,
A.Rusciani,
G.Jahreis,
A.S.Weiss,
R.H.Neubert,
and
C.E.Schmelzer
(2010).
Degradation of tropoelastin by matrix metalloproteinases--cleavage site specificities and release of matrikines.
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FEBS J,
277,
1939-1956.
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E.E.Chufán,
M.De,
B.A.Eipper,
R.E.Mains,
and
L.M.Amzel
(2009).
Amidation of bioactive peptides: the structure of the lyase domain of the amidating enzyme.
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Structure,
17,
965-973.
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PDB codes:
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I.Bertini,
M.Fragai,
C.Luchinat,
M.Melikian,
and
C.Venturi
(2009).
Characterisation of the MMP-12-elastin adduct.
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Chemistry,
15,
7842-7845.
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L.A.Cox
(2009).
A mathematical model of protease-antiprotease homeostasis failure in chronic obstructive pulmonary disease (COPD).
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Risk Anal,
29,
576-586.
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M.Rouffet,
C.Denhez,
E.Bourguet,
F.Bohr,
and
D.Guillaume
(2009).
In silico study of MMP inhibition.
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Org Biomol Chem,
7,
3817-3825.
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A.S.Dabert-Gay,
B.Czarny,
L.Devel,
F.Beau,
E.Lajeunesse,
S.Bregant,
R.Thai,
A.Yiotakis,
and
V.Dive
(2008).
Molecular Determinants of Matrix Metalloproteinase-12 Covalent Modification by a Photoaffinity Probe: INSIGHTS INTO ACTIVITY-BASED PROBE DEVELOPMENT AND CONFORMATIONAL VARIABILITY OF MATRIX METALLOPROTEINASES.
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J Biol Chem,
283,
31058-31067.
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J.W.Torrance,
M.W.Macarthur,
and
J.M.Thornton
(2008).
Evolution of binding sites for zinc and calcium ions playing structural roles.
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Proteins,
71,
813-830.
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P.Geurink,
T.Klein,
M.Leeuwenburgh,
G.van der Marel,
H.Kauffman,
R.Bischoff,
and
H.Overkleeft
(2008).
A peptide hydroxamate library for enrichment of metalloproteinases: towards an affinity-based metalloproteinase profiling protocol.
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Org Biomol Chem,
6,
1244-1250.
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R.Bhaskaran,
M.O.Palmier,
J.L.Lauer-Fields,
G.B.Fields,
and
S.R.Van Doren
(2008).
MMP-12 catalytic domain recognizes triple helical peptide models of collagen V with exosites and high activity.
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J Biol Chem,
283,
21779-21788.
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A.R.Johnson,
A.G.Pavlovsky,
D.F.Ortwine,
F.Prior,
C.F.Man,
D.A.Bornemeier,
C.A.Banotai,
W.T.Mueller,
P.McConnell,
C.Yan,
V.Baragi,
C.Lesch,
W.H.Roark,
M.Wilson,
K.Datta,
R.Guzman,
H.K.Han,
and
R.D.Dyer
(2007).
Discovery and characterization of a novel inhibitor of matrix metalloprotease-13 that reduces cartilage damage in vivo without joint fibroplasia side effects.
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J Biol Chem,
282,
27781-27791.
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PDB codes:
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F.E.Jacobsen,
J.A.Lewis,
and
S.M.Cohen
(2007).
The Design of Inhibitors for Medicinally Relevant Metalloproteins.
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ChemMedChem,
2,
152-171.
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R.Bhaskaran,
M.O.Palmier,
N.A.Bagegni,
X.Liang,
and
S.R.Van Doren
(2007).
Solution structure of inhibitor-free human metalloelastase (MMP-12) indicates an internal conformational adjustment.
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J Mol Biol,
374,
1333-1344.
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PDB code:
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D.Hesek,
M.Toth,
S.O.Meroueh,
S.Brown,
H.Zhao,
W.Sakr,
R.Fridman,
and
S.Mobashery
(2006).
Design and characterization of a metalloproteinase inhibitor-tethered resin for the detection of active MMPs in biological samples.
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Chem Biol,
13,
379-386.
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V.Sampath,
K.Davis,
A.P.Senft,
T.R.Richardson,
J.A.Kitzmiller,
P.Y.Berclaz,
and
T.R.Korfhagen
(2006).
Altered postnatal lung development in C3H/HeJ mice.
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Pediatr Res,
60,
663-668.
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I.Bertini,
V.Calderone,
M.Cosenza,
M.Fragai,
Y.M.Lee,
C.Luchinat,
S.Mangani,
B.Terni,
and
P.Turano
(2005).
Conformational variability of matrix metalloproteinases: beyond a single 3D structure.
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Proc Natl Acad Sci U S A,
102,
5334-5339.
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PDB codes:
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V.Lukacova,
Y.Zhang,
M.Mackov,
P.Baricic,
S.Raha,
J.A.Calvo,
and
S.Balaz
(2004).
Similarity of binding sites of human matrix metalloproteinases.
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J Biol Chem,
279,
14194-14200.
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H.I.Park,
Y.Jin,
D.R.Hurst,
C.A.Monroe,
S.Lee,
M.A.Schwartz,
and
Q.X.Sang
(2003).
The intermediate S1' pocket of the endometase/matrilysin-2 active site revealed by enzyme inhibition kinetic studies, protein sequence analyses, and homology modeling.
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J Biol Chem,
278,
51646-51653.
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W.Bode,
and
K.Maskos
(2003).
Structural basis of the matrix metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases.
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Biol Chem,
384,
863-872.
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W.Pan,
M.Arnone,
M.Kendall,
R.H.Grafstrom,
S.P.Seitz,
Z.R.Wasserman,
and
C.F.Albright
(2003).
Identification of peptide substrates for human MMP-11 (stromelysin-3) using phage display.
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J Biol Chem,
278,
27820-27827.
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D.V.Rozanov,
B.Ghebrehiwet,
T.I.Postnova,
A.Eichinger,
E.I.Deryugina,
and
A.Y.Strongin
(2002).
The hemopexin-like C-terminal domain of membrane type 1 matrix metalloproteinase regulates proteolysis of a multifunctional protein, gC1qR.
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J Biol Chem,
277,
9318-9325.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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Links
