 |
PDBsum entry 2v4b
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
 _NA
×4
|
|
|
|
|
|
|
|
|
|
|
 _ZN
×2
|
|
|
|
|
|
|
|
|
|
|
 _CD
×4
|
|
|
|
|
|
|
|
|
|
|
_NI
×14
|
|
|
|
|
|
|
|
|
|
|
 _MG
×3
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Crystal structures of human adamts-1 reveal a conserved catalytic domain and a disintegrin-Like domain with a fold homologous to cysteine-Rich domains.
|
|
|
Authors
|
|
S.Gerhardt,
G.Hassall,
P.Hawtin,
E.Mccall,
L.Flavell,
C.Minshull,
D.Hargreaves,
A.Ting,
R.A.Pauptit,
A.E.Parker,
W.M.Abbott.
|
|
|
Ref.
|
|
J Mol Biol, 2007,
373,
891-902.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
The ADAMTS (a disintegrin-like and metalloproteinase domain with thrombospondin
type I motifs) family of proteases plays a role in pathological conditions
including arthritis, cancer, thrombotic thrombocytopenic purpura and the
Ehlers-Danlos type VIIC and Weill-Marchesani genetic syndromes. Here, we report
the first crystal structures for a member of the ADAMTS family, ADAMTS-1.
Originally cloned as an inflammation-associated gene, ADAMTS-1 has been shown to
be involved in tissue remodelling, wound healing and angiogenesis. The crystal
structures contain catalytic and disintegrin-like domains, both in the
inhibitor-free form and in complex with the inhibitor marimastat. The overall
fold of the catalytic domain is similar to related zinc metalloproteinases such
as matrix metalloproteinases and ADAMs (a disintegrin and metalloproteinases).
The active site contains the expected organisation of residues to coordinate
zinc but has a much larger S1' selectivity pocket than ADAM33. The structure
also unexpectedly reveals a double calcium-binding site. Also surprisingly, the
previously named disintegrin-like domain showed no structural homology to the
disintegrin domains of other metalloproteinases such as ADAM10 but is instead
very similar in structure to the cysteine-rich domains of other
metalloproteinases. Thus, this study suggests that the D (for disintegrin-like)
in the nomenclature of ADAMTS enzymes is likely to be a misnomer. The ADAMTS-1
cysteine-rich domain stacks against the active site, suggesting a possible
regulatory role.
|
|
|
|
|
|
|
|
Figure 1.
Fig. 1. Domain structure representation for ADAMTS-1. Pre,
signal peptide; Pro, prodomain; metalloprotease, catalytic
domain; Dis, disintegrin-like; Cys, cysteine-rich domain; TS,
thrombospondin type I repeat; spacer, spacer domain.
|
|
Figure 3.
Fig. 3. (a) Secondary structure arrangement of the catalytic
metalloprotease domain (red and yellow) and of the cysteine-rich
domain (green) of ADAMTS-1 in complex with bound marimastat. The
catalytic zinc ion (purple) and two presumed cadmium ions bound
to the calcium-binding site (peach) are shown as spheres, while
the complexed marimastat ligand is shown as a ball-and-stick
model. Disulphide bonds are indicated. This and all other
molecular illustrations here were prepared using PyMol
[http://www.pymol.org]. (b) Structural superposition of human
ADAMTS-1 (red) and human ADAM33 (green) indicating the conserved
structure of the catalytic domain.
|
|
|
|
|
|
The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2007,
373,
891-902)
copyright 2007.
|
|
|
|
|
|
|
