 |
PDBsum entry 1bkc
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Zn-endopeptidase
|
PDB id
|
|
|
|
1bkc
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Crystal structure of the catalytic domain of human tumor necrosis factor-Alpha-Converting enzyme.
|
|
|
Authors
|
|
K.Maskos,
C.Fernandez-Catalan,
R.Huber,
G.P.Bourenkov,
H.Bartunik,
G.A.Ellestad,
P.Reddy,
M.F.Wolfson,
C.T.Rauch,
B.J.Castner,
R.Davis,
H.R.Clarke,
M.Petersen,
J.N.Fitzner,
D.P.Cerretti,
C.J.March,
R.J.Paxton,
R.A.Black,
W.Bode.
|
|
|
Ref.
|
|
Proc Natl Acad Sci U S A, 1998,
95,
3408-3412.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Tumor necrosis factor-alpha (TNFalpha) is a cytokine that induces protective
inflammatory reactions and kills tumor cells but also causes severe damage when
produced in excess, as in rheumatoid arthritis and septic shock. Soluble
TNFalpha is released from its membrane-bound precursor by a membrane-anchored
proteinase, recently identified as a multidomain metalloproteinase called
TNFalpha-converting enzyme or TACE. We have cocrystallized the catalytic domain
of TACE with a hydroxamic acid inhibitor and have solved its 2.0 A crystal
structure. This structure reveals a polypeptide fold and a catalytic zinc
environment resembling that of the snake venom metalloproteinases, identifying
TACE as a member of the adamalysin/ADAM family. However, a number of large
insertion loops generate unique surface features. The pro-TNFalpha cleavage site
fits to the active site of TACE but seems also to be determined by its position
relative to the base of the compact trimeric TNFalpha cone. The active-site
cleft of TACE shares properties with the matrix metalloproteinases but exhibits
unique features such as a deep S3' pocket merging with the S1' specificity
pocket below the surface. The structure thus opens a different approach toward
the design of specific synthetic TACE inhibitors, which could act as effective
therapeutic agents in vivo to modulate TNFalpha-induced pathophysiological
effects, and might also help to control related shedding processes.
|
|
|
|
|
|
|
|
Figure 1.
Fig. 1. Ribbon diagram of the TACE catalytic domain. The
chain starts and ends on the lower and upper left backside,
respectively. The three disulfides are shown as green
connections and the catalytic zinc is shown as a pink sphere.
His-405, His-409, His-415, Met-435, Pro-437, and the inhibitor
(white) are shown with their full structure. The figure was made
with SETOR (20).
|
|
Figure 5.
Fig. 5. Close-up view of the active-site cleft of TACE.
On top of the solid surface representing the proteinase the
bound inhibitor is shown in full structure, slotting with its
isobutyl (P1') and its Ala (P3') side chains into the deep S1'
and the novel S3' pockets. Figure was made as Fig. 2b (22).
|
|
|
|
|
|
|
|
|
|
