Substrate specificity determinants of human macrophage elastase (MMP-12) based on the 1.1 angstrom crystal structure
Lang R, Kocourek A, Braun M, Tschesche H, Huber R, Bode W, Maskos K (2001)
JOURNAL OF MOLECULAR BIOLOGY 312(4): 731-742.
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The macrophage elastase enzyme (MMP-12) expressed mainly in alveolar macrophages has been identified in the mouse lung as the main destructive agent associated with cigarette smoking, which gives rise to emphysema, both directly via elastin degradation and indirectly by disturbing the proteinase/antiproteinase balance via inactivation of the alpha1-proteinase inhibitor (alpha1-PI), the antagonist of the leukocyte elastase. The catalytic domain of human recombinant MMP-12 has been crystallized in complex with the broad-specificity inhibitor batimastat (BB-94). The crystal structure analysis of this complex, determined using X-ray data to 1.1 Angstrom and refined to an R-value of 0.165, reveals an overall fold similar to that of other MMPs. However, the S-shaped double loop connecting strands III and IV is fixed closer to the beta -sheet and projects its His172 side-chain further into the rather hydrophobic active-site cleft, defining the S3 and the S1-pockets and separating them from each other to a larger extent than is observed in other MMPs. The S2-site is planar, while the characteristic S1'-subsite is a continuous tube rather than a pocket, in which the MMP-12-specific Thr215 replaces a Val residue otherwise highly conserved in almost all other MMPs. This alteration might allow MMP-12 to accept P1' Arg residues, making it unique among MMPs. The active-site cleft of MMP-12 is well equipped to bind and efficiently cleave the AlaMetPhe-LeuGluAla sequence in the reactive-site loop of al-PI, as occurs experimentally. Similarities in contouring and particularly a common surface hydrophobicity both inside and distant from the active-site cleft explain why MMP-12 shares many substrates with matrilysin (MMP-7). The MMP-12 structure is an excellent template for the structure-based design of specific inhibitors for emphysema therapy and for the construction of mutants to clarify the role of this MMP. (C) 2001 Academic Press.
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Lang R, Kocourek A, Braun M, et al. Substrate specificity determinants of human macrophage elastase (MMP-12) based on the 1.1 angstrom crystal structure. JOURNAL OF MOLECULAR BIOLOGY. 2001;312(4):731-742.
Lang, R., Kocourek, A., Braun, M., Tschesche, H., Huber, R., Bode, W., & Maskos, K. (2001). Substrate specificity determinants of human macrophage elastase (MMP-12) based on the 1.1 angstrom crystal structure. JOURNAL OF MOLECULAR BIOLOGY, 312(4), 731-742. doi:10.1006/jmbi.2001.4954
Lang, R., Kocourek, A., Braun, M., Tschesche, H., Huber, R., Bode, W., and Maskos, K. (2001). Substrate specificity determinants of human macrophage elastase (MMP-12) based on the 1.1 angstrom crystal structure. JOURNAL OF MOLECULAR BIOLOGY 312, 731-742.
Lang, R., et al., 2001. Substrate specificity determinants of human macrophage elastase (MMP-12) based on the 1.1 angstrom crystal structure. JOURNAL OF MOLECULAR BIOLOGY, 312(4), p 731-742.
R. Lang, et al., “Substrate specificity determinants of human macrophage elastase (MMP-12) based on the 1.1 angstrom crystal structure”, JOURNAL OF MOLECULAR BIOLOGY, vol. 312, 2001, pp. 731-742.
Lang, R., Kocourek, A., Braun, M., Tschesche, H., Huber, R., Bode, W., Maskos, K.: Substrate specificity determinants of human macrophage elastase (MMP-12) based on the 1.1 angstrom crystal structure. JOURNAL OF MOLECULAR BIOLOGY. 312, 731-742 (2001).
Lang, R, Kocourek, A, Braun, M, Tschesche, Harald, Huber, R, Bode, W, and Maskos, K. “Substrate specificity determinants of human macrophage elastase (MMP-12) based on the 1.1 angstrom crystal structure”. JOURNAL OF MOLECULAR BIOLOGY 312.4 (2001): 731-742.
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x-ray diffraction (PDB: 1jk3)
Protein structure name: crystal structure of human mmp-12 (macrophage elastase) at true atomic resolution
Public wwPDB file in PDB format
Protein structure name: crystal structure of human mmp-12 (macrophage elastase) at true atomic resolution
Public wwPDB file in PDB format
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44 Citations in Europe PMC
Data provided by Europe PubMed Central.
Mapping of macrophage elastase cleavage sites in insoluble human skin elastin.
Taddese S, Weiss AS, Neubert RH, Schmelzer CE., Matrix Biol 27(5), 2008
PMID: 18334288
Taddese S, Weiss AS, Neubert RH, Schmelzer CE., Matrix Biol 27(5), 2008
PMID: 18334288
Substrate specificity of a metalloprotease of the pappalysin family revealed by an inhibitor and a product complex.
García-Castellanos R, Tallant C, Marrero A, Solà M, Baumann U, Gomis-Rüth FX., Arch Biochem Biophys 457(1), 2007
PMID: 17097044
García-Castellanos R, Tallant C, Marrero A, Solà M, Baumann U, Gomis-Rüth FX., Arch Biochem Biophys 457(1), 2007
PMID: 17097044
The design of inhibitors for medicinally relevant metalloproteins.
Jacobsen FE, Lewis JA, Cohen SM., ChemMedChem 2(2), 2007
PMID: 17163561
Jacobsen FE, Lewis JA, Cohen SM., ChemMedChem 2(2), 2007
PMID: 17163561
Calcium regulates tertiary structure and enzymatic activity of human endometase/matrilysin-2 and its role in promoting human breast cancer cell invasion.
Lee S, Park HI, Sang QX., Biochem J 403(1), 2007
PMID: 17176253
Lee S, Park HI, Sang QX., Biochem J 403(1), 2007
PMID: 17176253
Solution structure of inhibitor-free human metalloelastase (MMP-12) indicates an internal conformational adjustment.
Bhaskaran R, Palmier MO, Bagegni NA, Liang X, Van Doren SR., J Mol Biol 374(5), 2007
PMID: 17997411
Bhaskaran R, Palmier MO, Bagegni NA, Liang X, Van Doren SR., J Mol Biol 374(5), 2007
PMID: 17997411
Design and characterization of a metalloproteinase inhibitor-tethered resin for the detection of active MMPs in biological samples.
Hesek D, Toth M, Meroueh SO, Brown S, Zhao H, Sakr W, Fridman R, Mobashery S., Chem Biol 13(4), 2006
PMID: 16632250
Hesek D, Toth M, Meroueh SO, Brown S, Zhao H, Sakr W, Fridman R, Mobashery S., Chem Biol 13(4), 2006
PMID: 16632250
Synthesis of bicyclic molecular scaffolds (BTAa): an investigation towards new selective MMP-12 inhibitors.
Mannino C, Nievo M, Machetti F, Papakyriakou A, Calderone V, Fragai M, Guarna A., Bioorg Med Chem 14(22), 2006
PMID: 16899369
Mannino C, Nievo M, Machetti F, Papakyriakou A, Calderone V, Fragai M, Guarna A., Bioorg Med Chem 14(22), 2006
PMID: 16899369
Characterization of Ca2+ interactions with matrix metallopeptidase-12: implications for matrix metallopeptidase regulation.
Gossas T, Danielson UH., Biochem J 398(3), 2006
PMID: 16737445
Gossas T, Danielson UH., Biochem J 398(3), 2006
PMID: 16737445
Altered postnatal lung development in C3H/HeJ mice.
Sampath V, Davis K, Senft AP, Richardson TR, Kitzmiller JA, Berclaz PY, Korfhagen TR., Pediatr Res 60(6), 2006
PMID: 17065580
Sampath V, Davis K, Senft AP, Richardson TR, Kitzmiller JA, Berclaz PY, Korfhagen TR., Pediatr Res 60(6), 2006
PMID: 17065580
Structural basis for the highly selective inhibition of MMP-13.
Engel CK, Pirard B, Schimanski S, Kirsch R, Habermann J, Klingler O, Schlotte V, Weithmann KU, Wendt KU., Chem Biol 12(2), 2005
PMID: 15734645
Engel CK, Pirard B, Schimanski S, Kirsch R, Habermann J, Klingler O, Schlotte V, Weithmann KU, Wendt KU., Chem Biol 12(2), 2005
PMID: 15734645
Crystal structures of MMPs in complex with physiological and pharmacological inhibitors.
Maskos K., Biochimie 87(3-4), 2005
PMID: 15781312
Maskos K., Biochimie 87(3-4), 2005
PMID: 15781312
Future challenges facing the development of specific active-site-directed synthetic inhibitors of MMPs.
Cuniasse P, Devel L, Makaritis A, Beau F, Georgiadis D, Matziari M, Yiotakis A, Dive V., Biochimie 87(3-4), 2005
PMID: 15781327
Cuniasse P, Devel L, Makaritis A, Beau F, Georgiadis D, Matziari M, Yiotakis A, Dive V., Biochimie 87(3-4), 2005
PMID: 15781327
Conformational variability of matrix metalloproteinases: beyond a single 3D structure.
Bertini I, Calderone V, Cosenza M, Fragai M, Lee YM, Luchinat C, Mangani S, Terni B, Turano P., Proc Natl Acad Sci U S A 102(15), 2005
PMID: 15809432
Bertini I, Calderone V, Cosenza M, Fragai M, Lee YM, Luchinat C, Mangani S, Terni B, Turano P., Proc Natl Acad Sci U S A 102(15), 2005
PMID: 15809432
Structure-based design and synthesis of novel non-zinc chelating MMP-12 inhibitors.
Dublanchet AC, Ducrot P, Andrianjara C, O'Gara M, Morales R, Compère D, Denis A, Blais S, Cluzeau P, Courté K, Hamon J, Moreau F, Prunet ML, Tertre A., Bioorg Med Chem Lett 15(16), 2005
PMID: 16002291
Dublanchet AC, Ducrot P, Andrianjara C, O'Gara M, Morales R, Compère D, Denis A, Blais S, Cluzeau P, Courté K, Hamon J, Moreau F, Prunet ML, Tertre A., Bioorg Med Chem Lett 15(16), 2005
PMID: 16002291
Crystal structure of the catalytic domain of human matrix metalloproteinase 10.
Bertini I, Calderone V, Fragai M, Luchinat C, Mangani S, Terni B., J Mol Biol 336(3), 2004
PMID: 15095982
Bertini I, Calderone V, Fragai M, Luchinat C, Mangani S, Terni B., J Mol Biol 336(3), 2004
PMID: 15095982
Human meprin alpha and beta homo-oligomers: cleavage of basement membrane proteins and sensitivity to metalloprotease inhibitors.
Kruse MN, Becker C, Lottaz D, Köhler D, Yiallouros I, Krell HW, Sterchi EE, Stöcker W., Biochem J 378(pt 2), 2004
PMID: 14594449
Kruse MN, Becker C, Lottaz D, Köhler D, Yiallouros I, Krell HW, Sterchi EE, Stöcker W., Biochem J 378(pt 2), 2004
PMID: 14594449
Crystal structures of novel non-peptidic, non-zinc chelating inhibitors bound to MMP-12.
Morales R, Perrier S, Florent JM, Beltra J, Dufour S, De Mendez I, Manceau P, Tertre A, Moreau F, Compere D, Dublanchet AC, O'Gara M., J Mol Biol 341(4), 2004
PMID: 15289103
Morales R, Perrier S, Florent JM, Beltra J, Dufour S, De Mendez I, Manceau P, Tertre A, Moreau F, Compere D, Dublanchet AC, O'Gara M., J Mol Biol 341(4), 2004
PMID: 15289103
Structural basis of the matrix metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases.
Bode W, Maskos K., Biol Chem 384(6), 2003
PMID: 12887053
Bode W, Maskos K., Biol Chem 384(6), 2003
PMID: 12887053
Activity-based enrichment of matrix metalloproteinases using reversible inhibitors as affinity ligands.
Freije JR, Bischoff R., J Chromatogr A 1009(1-2), 2003
PMID: 13677656
Freije JR, Bischoff R., J Chromatogr A 1009(1-2), 2003
PMID: 13677656
58 References
Data provided by Europe PubMed Central.
SHELXL: high-resolution refinement.
Sheldrick GM, Schneider TR., Meth. Enzymol. 277(), 1997
PMID: 18488315
Sheldrick GM, Schneider TR., Meth. Enzymol. 277(), 1997
PMID: 18488315
The CCP4 suite,programs for protein crystallography
AUTHOR UNKNOWN, Acta Crystallog. sect. D 50(), 1994
AUTHOR UNKNOWN, Acta Crystallog. sect. D 50(), 1994
McRee, 1993
PROCHECK: a program to check the stereochemical quality of protein structures.
Laskowski RA, MacArthur MW, Moss DS, Thornton JM., J Appl Crystallogr 26(2), 1993
PMID: c6802
Laskowski RA, MacArthur MW, Moss DS, Thornton JM., J Appl Crystallogr 26(2), 1993
PMID: c6802
An extensively modified version of MolScript that includes greatly enhanced coloring capabilities.
Esnouf RM., J. Mol. Graph. Model. 15(2), 1997
PMID: 9385560
Esnouf RM., J. Mol. Graph. Model. 15(2), 1997
PMID: 9385560
Raster3D version 2.0. A program for photorealistic molecular graphics
Merritt, Acta Crystallog. sect. D 50(), 1994
Merritt, Acta Crystallog. sect. D 50(), 1994
ALSCRIPT: a tool to format multiple sequence alignments.
Barton GJ., Protein Eng. 6(1), 1993
PMID: 8433969
Barton GJ., Protein Eng. 6(1), 1993
PMID: 8433969
Swiss-PDBViewer
Guex, PDB Quart. Newsletter 77(), 1996
Guex, PDB Quart. Newsletter 77(), 1996
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