PDBsum entry 1gxd

Hydrolase

PDB id: 1gxd

Contents

Protein chains

624 a.a. *

192 a.a. *

Ligands

SO4 ×2

Metals

_CA ×2

_ZN ×4

* Residue conservation analysis

References listed in PDB file

Key reference

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

Abstract

Matrix metalloproteinases (MMPs) are a family of multidomain enzymes involved in the physiological degradation of connective tissue, as well as in pathological states such as tumor invasion and arthritis. Apart from transcriptional regulation, MMPs are controlled by proenzyme activation and a class of specific tissue inhibitors of metalloproteinases (TIMPs) that bind to the catalytic site. TIMP-2 is a potent inhibitor of MMPs, but it has also been implicated in a unique cell surface activation mechanism of latent MMP-2/gelatinase A/type IV collagenase (proMMP-2), through its binding to the hemopexin domain of proMMP-2 on the one hand and to a membrane-type MMP activator on the other. The present crystal structure of the human proMMP-2/TIMP-2 complex reveals an interaction between the hemopexin domain of proMMP-2 and the C-terminal domain of TIMP-2, leaving the catalytic site of MMP-2 and the inhibitory site of TIMP-2 distant and spatially isolated. The interfacial contact of these two proteins is characterized by two distinct binding regions composed of alternating hydrophobic and hydrophilic interactions. This unique structure provides information for how specificity for noninhibitory MMP/TIMP complex formation is achieved.

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.