Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1.
Abstract
Matrix metalloproteinases (MMPs) are zinc endopeptidases that are required for the degradation of extracellular matrix components during normal embryo development, morphogenesis and tissue remodelling. Their proteolytic activities are precisely regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). Disruption of this balance results in diseases such as arthritis, atherosclerosis, tumour growth and metastasis. Here we report the crystal structure of an MMP-TIMP complex formed between the catalytic domain of human stromelysin-1 (MMP-3) and human TIMP-1. TIMP-1, a 184-residue protein, has the shape of an elongated, contiguous wedge. With its long edge, consisting of five different chain regions, it occupies the entire length of the active-site cleft of MMP-3. The central disulphide-linked segments Cys 1-Thr 2-Cys 3-Val 4 and Ser 68-Val 69 bind to either side of the catalytic zinc. Cys 1 bidentally coordinates this zinc, and the Thr-2 side chain extends into the large specificity pocket of MMP-3. This unusual architecture of the interface between MMP-3 and TIMP-1 suggests new possibilities for designing TIMP variants and synthetic MMP inhibitors with potential therapeutic applications.
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TIMPs form 1:1 complexes with MMPs in order to inhibit MMP activity.
“tissue inhibitors of MMPs, known as TIMPs, which form 1:1 complexes with MMPs in order to inhibit MMP activity (Gomis-Rüth et al., 1997; Brew and Nagase, 2010).”
From The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders (2018) · cites this paper as Gomis-Rüth et al., 1997
These tyrosine residues reside near key disulfide bonds forming knot structures critical for TIMP-1 binding and MMP inhibition.
“These tyrosine residues reside near key disulfide bonds that form knot structures, which are critical for TIMP-1 binding and inhibition of active MMPs [287].”
From Signaling and stress: The redox landscape in NOS2 biology (2015) · cites this paper as [287]
Cites
AMoRe: an automated package for molecular replacement
Navaza, J. (1994) · Acta Crystallographica Section A Foundations of Crystallography · doi:10.1107/s0108767393007597 · Cited by 4,941 · see citing works
A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells
Black, R. A., Rauch, C. T., Kozlosky, C. J., Peschon, J. J., Slack, J. L., Wolfson, M. F., Castner, B. J., Stocking, K. L., Reddy, P., Srinivasan, S., et al. (1997) · Nature · doi:10.1038/385729a0 · Cited by 3,149 · see citing works
Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-α
Moss, M. L., Jin, S.-L. C., Milla, M. E., Burkhart, W., Carter, H. L., Chen, W., Clay, W. C., Didsbury, J. R., Hassler, D. F., Hoffman, C. R., et al. (1997) · Nature · doi:10.1038/385733a0 · Cited by 1,611 · see citing works
Murzin, A. G. (1993) · The EMBO Journal · doi:10.1002/j.1460-2075.1993.tb05726.x · Cited by 924 · see citing works
Stöcker, W., Grams, F., Reinemer, P., Bode, W., Baumann, U., Gomis‐Rüth, F. X., & McKay, D. (1995) · Protein Science · doi:10.1002/pro.5560040502 · Cited by 725 · see citing works
Self-citationDocherty, A., Lyons, A., Smith, B. J., Wright, E. M., Stephens, P. E., Harris, T. J. R., Murphy, G., & Reynolds, J. J. (1985) · Nature · doi:10.1038/318066a0 · Cited by 689 · see citing works
Matrix metal loproteinases and the development of cancer
Coussens, L. M., & Werb, Z. (1996) · Chemistry & Biology · doi:10.1016/s1074-5521(96)90178-7 · Cited by 569 · see citing works
Will, H., Atkinson, S. J., Butler, G. S., Smith, B., & Murphy, G. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.29.17119 · Cited by 566 · see citing works
Molecular Cloning and Characterization of Human Tissue Inhibitor of Metalloproteinase 4
Greene, J., Wang, M., Liu, Y. E., et al. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.48.30375 · Cited by 558 · see citing works
Bone Morphogenetic Protein-1: The Type I Procollagen C-Proteinase
Kessler, E., Takahara, K., Biniaminov, L., Brusel, M., & Greenspan, D. S. (1996) · Science · doi:10.1126/science.271.5247.360 · Cited by 538 · see citing works
Baumann, U., Wu, S., Flaherty, K. M., & McKay, D. (1993) · The EMBO Journal · doi:10.1002/j.1460-2075.1993.tb06009.x · Cited by 473 · see citing works
Structure of astacin and implications for activation of astacins and zinc-ligation of collagenases
Bode, W., Gomis‐Rüth, F. X., Huber, R., Zwilling, R., & Stöcker, W. (1992) · Nature · doi:10.1038/358164a0 · Cited by 333 · see citing works
Self-citationMurphy, G., Houbrechts, A., Cockett, M. I., Williamson, R. A., O'Shea, M., & Docherty, A. (1991) · Biochemistry · doi:10.1021/bi00247a001 · Cited by 325 · see citing works
Becker, J. W., Marcy, A. I., Rokosz, L. L., Axel, M. G., Burbaum, J. J., Fitzgerald, P. M. D., Cameron, P. M., Esser, C. K., Hagmann, W. K., Hermes, J. D., et al. (1995) · Protein Science · doi:10.1002/pro.5560041002 · Cited by 293 · see citing works
Li, J., Brick, P., O'Hare, M., et al. (1995) · Structure · doi:10.1016/s0969-2126(01)00188-5 · Cited by 261 · see citing works
Zinc Metalloproteases In Health And Disease
(1996) · CRC Press eBooks · doi:10.1201/9781482272765 · Cited by 221 · see citing works
Gomis‐Rüth, F. X., Kress, L. F., & Bode, W. (1993) · The EMBO Journal · doi:10.1002/j.1460-2075.1993.tb06099.x · Cited by 216 · see citing works
Self-citationGrams, F., Reinemer, P., Powers, J. C., Kleine, T., Pieper, M. P., Tschesche, H., Huber, R., & Bode, W. (1995) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1995.tb20329.x · Cited by 180 · see citing works
Self-citationThe NMR structure of the inhibited catalytic domain of human stromelysin–1
Gooley, P. R., O’Connell, J. F., Marcy, A. I., Cuca, G. C., Salowe, S. P., Bush, B. L., Hermes, J. D., Esser, C. K., Hagmann, W. K., Springer, J. P., et al. (1994) · Nature Structural & Molecular Biology · doi:10.1038/nsb0294-111 · Cited by 154 · see citing works
Huovila, A.-P. J., Almeida, E. A. C., & White, J. M. (1996) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(96)80111-6 · Cited by 139 · see citing works
Dhanaraj, V., Ye, Q.-Z., Johnson, L., et al. (1996) · Structure · doi:10.1016/s0969-2126(96)00043-3 · Cited by 117 · see citing works
Williamson, R. A., Martorell, G., Carr, M. D., et al. (1994) · Biochemistry · doi:10.1021/bi00205a010 · Cited by 107 · see citing works
Huang, W., Suzuki, K., Nagase, H., Arumugan, S., Doren, S. R. V., & Brew, K. (1996) · FEBS Letters · doi:10.1016/0014-5793(96)00304-3 · Cited by 102 · see citing works
Self-citationStructure-Function Relationships in the Tissue Inhibitors of Metalloproteinases
Willenbrock, F. W., & Murphy, G. (1994) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/ajrccm/150.6_pt_2.s165 · Cited by 99 · see citing works
Crystallographic phasing and refinement of macromolecules
Brünger, A. T. (1991) · Current Opinion in Structural Biology · doi:10.1016/0959-440x(91)90100-8 · Cited by 23 · see citing works
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Visse, R., & Nagase, H. (2003) · Circulation Research · doi:10.1161/01.res.0000070112.80711.3d · Cited by 4,575 · see citing works
Self-citationHow Matrix Metalloproteinases Regulate Cell Behavior
Sternlicht, M. D., & Werb, Z. (2001) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.17.1.463 · Cited by 3,959 · see citing works
Strategies for MMP inhibition in cancer: innovations for the post-trial era
Overall, C. M., & López-Otín, C. (2002) · Nature Reviews Cancer · doi:10.1038/nrc884 · Cited by 1,349 · see citing works
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Liu, Y., Tjäderhane, L., Breschi, L., Mazzoni, A., Li, N., Mao, J., Pashley, D. H., & Tay, F. R. (2011) · Journal of Dental Research · doi:10.1177/0022034510391799 · Cited by 665 · see citing works
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Yu, W.-H., Yu, S.-S. C., Meng, Q., Brew, K., & Woessner, J. F. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m000907200 · Cited by 328 · see citing works
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Beroun, A., Mitra, S., Michaluk, P., Pijet, B., Stefaniuk, M., & Kaczmarek, L. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03180-8 · Cited by 207 · see citing works
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Wen, T. H., Binder, D. K., Ethell, I. M., & Razak, K. A. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00270 · Cited by 170 · see citing works
Signaling and stress: The redox landscape in NOS2 biology
Thomas, D. D., Heinecke, J. L., Ridnour, L. A., Cheng, R. Y., Kesarwala, A. H., Switzer, C. H., McVicar, D. W., Roberts, D. D., Glynn, S., Fukuto, J. M., et al. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.002 · Cited by 150 · see citing works
The Design of Inhibitors for Medicinally Relevant Metalloproteins
Jacobsen, F. E., Lewis, J. A., & Cohen, S. M. (2007) · ChemMedChem · doi:10.1002/cmdc.200600204 · Cited by 132 · see citing works
Crystal Structure of the Catalytic Domain of Human ADAM33
Orth, P., Reichert, P., Wang, W., Prosise, W. W., Yarosh-Tomaine, T., Hammond, G., Ingram, R. N., Xiao, L., Mirza, U. A., Zou, J., et al. (2004) · Journal of Molecular Biology · doi:10.1016/j.jmb.2003.10.037 · Cited by 90 · see citing works
- Authors
- Gomis-R¨th, F.-X., Maskos, K., Betz, M., Bergner, A., Huber, R., Suzuki, K., Yoshida, N., Nagase, H., Brew, K., Bourenkov, G. P., Bartunik, H., & Bode, W.
- Affiliations
- Max Planck Institute of Biochemistry (DE)
- University of Kansas Medical Center (US)
- University of Miami (US)
- Deutsches Elektronen-Synchrotron DESY (DE)
- Corresponding author
- Bode, Wolfram
- ORCID
- Venue
- Nature
- Published
- 1997-09
- Volume
- 389
- Issue
- 6646
- Pages
- 77-81
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1928161708
- Cited by
- 619
- References
- 25
- Citations by year
- 2026: 5 · 2025: 15 · 2024: 15 · 2023: 11 · 2022: 20 · 2021: 16 · 2020: 11 · 2019: 12 · 2018: 15 · 2017: 18 · 2016: 17 · 2015: 21 · 2014: 12 · 2013: 25 · 2012: 26
- FWCI
- 14.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DESY Publication Database (PUBDB) (Deutsches Elektronen-Synchrotron) (submittedVersion)
- Funders
- Bundesministerium für Bildung und Forschung
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- stromelysin-1, TIMP-1, tissue inhibitors of metalloproteinases, matrix metalloproteinase inhibition, zinc metalloprotease, OB-fold, protein-protein interaction, metastasis, extracellular matrix remodeling, protease inhibitors, structure-function relationship, N-terminal domain, catalytic cysteine
- MeSH terms
- Binding Sites, Glycoproteins, Glycosylation, Humans, Models, Molecular, Protease Inhibitors, Protein Conformation, Drug Design, Crystallography, X-Ray, Matrix Metalloproteinase 3, Tissue Inhibitor of Metalloproteinases, Matrix Metalloproteinase Inhibitors
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