PDBsum entry 3ba0

Hydrolase

PDB id: 3ba0

Contents

Protein chain

365 a.a.

Ligands

HAE

Metals

_ZN ×2

_CA ×4

Waters ×62

References listed in PDB file

Key reference

Title

Evidence of reciprocal reorientation of the catalytic and hemopexin-Like domains of full-Length mmp-12.

Authors

I.Bertini, V.Calderone, M.Fragai, R.Jaiswal, C.Luchinat, M.Melikian, E.Mylonas, D.I.Svergun.

Ref.

J Am Chem Soc, 2008, 130, 7011-7021.

PubMed id

18465858

Abstract

The proteolytic activity of matrix metalloproteinases toward extracellular matrix components (ECM), cytokines, chemokines, and membrane receptors is crucial for several homeostatic and pathological processes. Active MMPs are a family of single-chain enzymes (23 family members in the human genome), most of which constituted by a catalytic domain and by a hemopexin-like domain connected by a linker. The X-ray structures of MMP-1 and MMP-2 suggest a conserved and well-defined spatial relationship between the two domains. Here we present structural data for MMP-12, suitably stabilized against self-hydrolysis, both in solution (NMR and SAXS) and in the solid state (X-ray), showing that the hemopexin-like and the catalytic domains experience conformational freedom with respect to each other on a time scale shorter than 10(-8) s. Hints on the probable conformations are also obtained. This experimental finding opens new perspectives for the often hypothesized active role of the hemopexin-like domain in the enzymatic activity of MMPs.

Secondary reference #1

Title

X-Ray structure of human prommp-1: new insights into procollagenase activation and collagen binding.

Authors

D.Jozic, G.Bourenkov, N.H.Lim, R.Visse, H.Nagase, W.Bode, K.Maskos.

Ref.

J Biol Chem, 2005, 280, 9578-9585. [DOI no: 10.1074/jbc.M411084200]

PubMed id

15611040

Figure 4.
FIG. 4. Interaction between the prodomain and the Hpx domain in proMMP-1. A, electron density figure of molecule A. The final 2.2 Å electron density is contoured at 1 , and the residues are shown as stick models in atom type. The figure was made with MAIN (24). B, interactions between the pro- and Hpx domains seen in molecule A of the asymmetric unit. Residues involved in the interaction between the prodomain (blue ribbon) and the Hpx domain (green ribbon) are shown as sticks and are labeled. Hydrogen bonds are shown as green dotted lines. The figure was made with the Swiss-PDB viewer (49).

Figure 6.
FIG. 6. The Hpx domain in pro- and active MMP-1 has a different conformation. A, both molecules of the asymmetric unit superimposed on their catalytic domains (dark pink, molecule A; green, molecule B). Note the difference in Hpx domain orientation. B, molecule B superimposed with active porcine MMP-1 (18), superimposed on the catalytic domain (cat). Molecule B is shown in green; active MMP-1 (Protein Data Bank accession code 1FBL [PDB] , porcine MMP-1) is shown in pink. C, same as B but rotated to show the difference of the catalytic-Hpx domain conformation in proMMP-1 and active MMP-1. The curved arrow indicates the relative movement between pro- and active MMP-1. The straight arrow indicates the cleft between the catalytic domain and the Hpx domain that is closed in proMMP-1 and open in active MMP-1. This figure was made with the Swiss-PDB viewer (49).

The above figures are reproduced from the cited reference with permission from the ASBMB

Secondary reference #2

Title

Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2.

Authors

E.Morgunova, A.Tuuttila, U.Bergmann, K.Tryggvason.

Ref.

Proc Natl Acad Sci U S A, 2002, 99, 7414-7419. [DOI no: 10.1073/pnas.102185399]

PubMed id

12032297

Figure 1.
Fig. 1. Structure of the proMMP-2/TIMP-2 complex. Overall conformation: the proteinase and inhibitor interact via their C-terminal domains. The catalytic site of MMP-2 and the inhibitory active site of TIMP-2 are turned away from each other. This topology excludes an inhibitory interaction between the proteinase and inhibitor and implies that both proteins remain fully functional in the complex. Catalytic and structural Zn2+ ions are colored red and Ca^2+ ion purple. The -propeller blades of the hemopexin domain are numbered from I to IV. Two light blue ellipsoids in blades III and IV indicate two areas of interaction between proMMP-2 and TIMP-2 molecules.

Figure 4.
Fig. 4. Stereo ribbon diagram of the hypothetical model of complex formed between proMMP-2, TIMP-2, and the catalytic domain of MT1-MMP. In the model shown, TIMP-2 is a hybrid with its C-terminal domain taken from the presented proMMP-2/TIMP-2 complex structure (magenta) and the N-terminal TIMP-2 half (red) is obtained from the model of the MT1-MMP/TIMP-2 inhibitory complex (Protein Data Bank code 1BUV) (26). Such combining was done because of the structural differences between complexed and uncomplexed forms of TIMP-2 molecules. Coloring for proMMP-2: the propeptide is pink, catalytic domain is blue, three fibronectin-like domains are green, and the hemopexin domain is yellow; for MT1-MMP: the catalytic domain is light blue.