 |
PDBsum entry 1jk3
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Substrate specificity determinants of human macrophage elastase (mmp-12) based on the 1.1 a crystal structure.
|
|
|
Authors
|
|
R.Lang,
A.Kocourek,
M.Braun,
H.Tschesche,
R.Huber,
W.Bode,
K.Maskos.
|
|
|
Ref.
|
|
J Mol Biol, 2001,
312,
731-742.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
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.
|
|
|
|
|
|
|
|
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]
|
|
Figure 4.
|
|
|
|
|
|
The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2001,
312,
731-742)
copyright 2001.
|
|
|
|
|
|
|
