Matrix Metalloproteinase Biology

Discussing recent advances in the field of matrix metalloproteinase (MMP) research from a multidisciplinary perspective, Matrix Metalloproteinase Biologyis a collection of chapters written by leaders in the field of MMPs. The book focuses on the challenges of understanding the mechanisms substrate degradation by MMPs, as well as how these enzymes are able to degrade large, highly ordered substrates such as collagen. All topics addressed are considered in relation to disease progression including roles in cancer metastasis, rheumatoid arthritis and other inflammatory diseases.

The text first provides an overview of MMPs, focusing on the history, the development and failures of small molecule inhibitors in clinical trials, and work with TIMPS, the endogenous inhibitors of MMPs. These introductory chapters establish the foundation for later discussion of the recent progress on the design of different types of inhibitors, including novel antibody based therapeutics. The following section emphasizes research using novel methods to further the study of the MMPs. The third and final section focuses on in vivo research, particularly with respect to cancer models, degradation of the extracellular matrix, and MMP involvement in other disease states.
Written and edited by leaders in the field, Matrix Metalloproteinase Biology addresses the rapidly growth in MMP research, and will be an invaluable resource to advanced students and researchers studying cell and molecular biology.

Auteur
Irit Sagi is Incumbent of the Maurizio Pontecorvo Professorial Chair in the Department of Biological Regulation at the Weizmann Institute of Science, Rehovot, Israel.

Jean P. Gaffney completed her postdoctoral work in Dr. Sagi's laboratory at the Weizmann Institute of Science, Rehovot, Israel. She is an Assistant Professor of Chemistry at Baruch College, City University of New York, New York, NY, USA.

Contenu

List of Contributors ix

**1 Matrix Metalloproteinases: From Structure to Function 1
**Maciej J. Stawikowski and Gregg B. Fields

1.1 Introduction 1

1.2 Structures of MMPs 1

1.2.1 General MMP structure and domain organization 1

1.2.2 Catalytic domain 2

1.2.3 Catalytic mechanism 3

1.2.4 Fibronectin type II-like inserts 3

1.2.5 Linker region 4

1.2.6 Hemopexin-like domain 6

1.2.7 Transmembrane domain and cytoplasmic tail 7

1.3 Overview of MMP substrate specificity 8

1.3.1 ECM substrates 9

1.3.2 Cell surface substrates 10

1.3.3 Intracellular MMP targets 11

1.4 Selective mechanisms of action 13

1.4.1 Collagenolysis 13

1.4.2 Gelatinolysis 15

Acknowledgments 16

References 16

**2 Dynamics and Mechanism of Substrate Recognition by Matrix Metalloproteases 23
**Ivan E. Collier and Gregory I. Goldberg

2.1 Introduction 23

2.2 Conformational flexibility of MMPs is inexorably linked to collagen proteolysis 24

2.3 Dynamics of MMP-2 and MMP-9 interaction with gelatin 26

2.4 Surface diffusion: a common mechanism for substrate interaction adapted by MMP-2 and MMP-9 26

2.5 Dynamics of MMP interaction with collagen fibrils 28

2.6 Mechanism of interaction of MMP-1, MMP-2, MMP-9, and MMP-14 with collagen substrate involves surface diffusion 28

2.7 Mechanism of MMP-1 diffusion on native collagen fibrils 30

2.8 Triple helical collagen cleavage diffusion coupling 31

2.9 Conclusions 34

References 36

**3 Matrix Metalloproteinases: From Structure to Function 41
**Marco Fragai and Claudio Luchinat

3.1 Introduction 41

3.2 Classification and structural features 42

3.3 Catalytic mechanism 45

3.4 Intra- and inter-domain flexibility 47

3.5 Elastin and collagen degradation 47

References 54

**4 Metzincin Modulators 61
**Dmitry Minond

4.1 Inhibitors 61

4.1.1 Antibodies: targeting beyond the active site 61

4.1.2 Peptide-based inhibitors 65

4.1.3 Small molecules: non-zinc binding exosite inhibitors 68

4.1.4 Protein-based inhibitors 78

Summary and future directions 80

References 81

**5 Therapeutics Targeting Matrix Metalloproteinases 85
**Jillian Cathcart, Ashleigh Pulkoski-Gross, Stanley Zucker, and Jian Cao

5.1 Introduction 85

5.2 Peptidomimetic MMP inhibitors 86

5.3 Structure-based MMPI drug design 87

5.4 Mechanism-based MMPI design 89

5.5 Allosteric MMPI design 90

5.6 Macromolecular MMP inhibitors 91

5.7 Chemically-modified tetracyclines 93

5.8 Alternative approaches 94

5.9 MMPs as anti-targets 95

5.10 Conclusions 97

References 98

**6 Matrix Metalloproteinase Modification of Extracellular Matrix-Mediated Signaling 103
**Howard C. Crawford and Sharon M. Stack

6.1 Introduction 103

6.2 The extracellular matrix as a source for signaling ligands 104

6.3 ECM and mechanosensory signal transduction 106

6.4 Matrix remodeling and modification of mechano-sensory signaling 108

6.5 Conclusions and future directions 109

References 109

**7 Meprin and ADAM Metalloproteases: Two Sides of the Same Coin? 115
**Christoph Becker-Pauly and Stefan Rose-John

7.1 Introduction 115

7.2 Meprin metalloproteases 116

7.3 Structure of meprin and meprin 116

7.4 Proteomics for the identification of meprin substrates 118

7.5 Meprins in health and disease 118

7.6 Proteolytic back-and-forth of meprins and ADAMs 119

7.7 Collagen fibril formation 119 7.8 Angiogenesis and cancer ...