PDBsum entry 1bkc

Zn-endopeptidase

PDB id: 1bkc

Contents

Protein chains

255 a.a. *

Ligands

INN ×4

Metals

_ZN ×4

Waters ×1620

* Residue conservation analysis

PDB id:

1bkc

Name:

Zn-endopeptidase

Title:

Catalytic domain of tnf-alpha converting enzyme (tace)

Structure:

Tumor necrosis factor-alpha-converting enzyme. Chain: a, c. Synonym: tace. Engineered: yes. Mutation: yes. Tumor necrosis factor-alpha-converting enzyme. Chain: e. Synonym: tace. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Organism_taxid: 9606

Resolution:

2.00Å R-factor: 0.180 R-free: 0.270

Authors:

K.Maskos,C.Fernandez-Catalan,W.Bode

Key ref:

K.Maskos et al. (1998). Crystal structure of the catalytic domain of human tumor necrosis factor-alpha-converting enzyme. Proc Natl Acad Sci U S A, 95, 3408-3412. PubMed id: 9520379 DOI: 10.1073/pnas.95.7.3408

Date:

23-Apr-98 Release date: 22-Jun-99

Protein chains

P78536  (ADA17_HUMAN) -  Disintegrin and metalloproteinase domain-containing protein 17 from Homo sapiens

Seq: 824 a.a.

Struc: 255 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.4.24.86 - Adam 17 endopeptidase.
• Cofactor: Zn(2+)

DOI no: 10.1073/pnas.95.7.3408

Proc Natl Acad Sci U S A 95:3408-3412 (1998)

PubMed id: 9520379

Crystal structure of the catalytic domain of human tumor necrosis factor-alpha-converting enzyme.

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.

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.

Selected figure(s)

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).

Figures were selected by the author.