Structure of astacin and implications for activation of astacins and zinc-ligation of collagenases

Bode, Wolfram; Gomis-Rüth, Franz-Xaver; Huber, Robert; Zwilling, Robert; Stöcker, Walter

doi:10.1038/358164a0

Cited by 320 publications

(261 citation statements)

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“…The active site zinc coordination by three histidyl nitrogen ligands was expected because of the homology with the zinc endopeptidase astacin, whose structure was solved (Bode et al, 1992). This was verified for collagenases by crystallography and for stromelysin by diagnostic imidazole chemical shifts (Gooley et al, 1993).…”

Section: Role Of Metalmentioning

confidence: 87%

“…A representative of the MMPs, the catalytic domain of human stromelysin was shown by NMR to contain three helices and a five-stranded mixed 0-sheet (Gooley et al, 1993;, organized in a fold similar to that of crayfish astacin (Bode et al, 1992). The zinc-binding motif at the active site, containing the conserved HEXXHXXGXXH sequence, as well as a conserved methionine in a turn adjacent to the catalytic zinc, are also shared with astacin.…”

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confidence: 99%

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Solution structure of the catalytic domain of human stromelysin complexed with a hydrophobic inhibitor

Doren

Kurochkin

et al. 1995

Protein Science

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Stromelysin, a representative matrix metalloproteinase and target of drug development efforts, plays a prominent role in the pathological proteolysis associated with arthritis and secondarily in that of cancer metastasis and invasion. To provide a structural template to aid the development of therapeutic inhibitors, we have determined a medium-resolution structure of a 20-kDa complex of human stromelysin's catalytic domain with a hydrophobic peptidic inhibitor using multinuclear, multidimensional NMR spectroscopy. This domain of this zinc hydrolase contains a mixed 0-sheet comprising one antiparallel strand and four parallel strands, three helices, and a methionine-containing turn near the catalytic center. The ensemble of 20 structures was calculated using, on average, 8 interresidue NOE restraints per residue for the 166-residue protein fragment complexed with a 4-residue substrate analogue. The mean RMS deviation (RMSD) to the average structure for backbone heavy atoms is 0.91 A and for all heavy atoms is 1.42 A. The structure has good stereochemical properties, including its backbone torsion angles. The &sheet and a-helices of the catalytic domains of human stromelysin (NMR model) and human fibroblast collagenase (X-ray crystallographic model of Lovejoy B et al., 1994b, Biochemisfry 33:8207-8217) superimpose well, having a pairwise RMSD for backbone heavy atoms of 2.28 A when three loop segments are disregarded. The hydroxamate-substituted inhibitor binds across the hydrophobic active site of stromelysin in an extended conformation. The first hydrophobic side chain is deeply buried in the principal Si subsite, the second hydrophobic side chain is located on the opposite side of the inhibitor backbone in the hydrophobic Si surface subsite, and a third hydrophobic side chain (Pi) lies at the surface.Keywords: catalytic domain; hydroxamate; matrix metalloproteinase 3; multidimensional NMR; protein structure; stromelysinAs a member of the zinc-and calcium-dependent family of matrix metalloproteinases (MMPs), which hydrolyze the extracellular matrix, stromelysin participates in the tissue remodeling of health and disease. Regarding the shared domain structure of the MMPs, their subfamilies, specificity, transcriptional regulation, activation, and posttranslational regulation, see reviews of Woessner (1991), Matrisian (1992), Birkedal-Hansen et al. (1993), andNagase (1995). The involvement of MMPs in tissue remodeling includes that of development, tissue resorption, reproduction, angiogenesis, and wound healing, and that of sev-

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Section: Role Of Metalmentioning

confidence: 87%

mentioning

confidence: 99%

Solution structure of the catalytic domain of human stromelysin complexed with a hydrophobic inhibitor

Doren

Kurochkin

et al. 1995

Protein Science

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“…The X-ray crystal structure of astacin has been solved to 1.8 A resolution (Bode et al, 1992). Astacin has a compact bilobal structure with a long, deep active-site cleft that divides it into two parts (Fig.…”

Section: Tertiary Structure Of the Protease Domainmentioning

confidence: 99%

“…Ribbon structure of astacin. Images were produced from the PDB file lAST (Bode et al, 1992) using the program SETOR (Evans, 1993). This view looks into the active site cleft, which runs from left to right in the image.…”

Section: Oligomeric Structure and Membrane Associationmentioning

confidence: 99%

“…The family was named the "astacin family" because a protease from the crayfish Astacus astacus L., the enzyme now called astacin (EC 3.4.24.21), was the first to be sequenced and biochemically characterized (Titani et al, 1987). It has subsequently been crystallized and the three-dimensional structure solved, adding a new dimension to our understanding and exploration of these metalloendopeptidases (Bode et al, 1992). Since the discovery of this family, 17 additional members have been cloned and sequenced, and there is evidence for others.…”

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The astacin family of metalloendopeptidases

1995

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The astacin family of metalloendopeptidases was recognized as a novel family of proteases in the 1990s. The crayfish enzyme astacin was the first characterized and is one of the smallest members of the family. More than 20 members of the family have now been identified. They have been detected in species ranging from hydra to humans, in mature and in developmental systems. Proposed functions of these proteases include activation of growth factors, degradation of polypeptides, and processing of extracellular proteins. Astacin family proteases are synthesized with NH,-terminal signal and proenzyme sequences, and many (such as meprins, BMP-1, folloid) contain multiple domains COOH-terminal to the protease domain. They are either secreted from cells or are plasma membrane-associated enzymes. They have some distinguishing features in addition to the signature sequence in the protease domain: HEXXHXXGFXHEXXRXDR. They have a unique type of zinc binding, with pentacoordination, and a protease domain tertiary structure that contains common attributes with serralysins, matrix metalloendopeptidases, and snake venom proteases; they cleave peptide bonds in polypeptides such as insulin B chain and bradykinin and in proteins such as casein and gelatin; and they have arylamidase activity. Meprins are unique proteases in the astacin family, and indeed in the animal kingdom, in their oligomeric structure; they are dimers of disulfide-linked dimers and are highly glycosylated, type I integral membrane proteins that have many attributes of receptors or integrins with adhesion, epidermal growth factor-like, and transmembrane domains. The 01 and /3 subunits are differentially expressed and processed to yield latent and active proteases as well as membraneassociated and secreted forms. Meprins represent excellent models of hetero-and homo-oligomeric enzymes that are regulated at the transcriptional and posttranslational levels.

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Zinc Complexes of Tripodal N3O Ligands

Trösch

Vahrenkamp²

1998

Eur. J. Inorg. Chem.

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Structure of astacin and implications for activation of astacins and zinc-ligation of collagenases

Cited by 320 publications

References 27 publications

Solution structure of the catalytic domain of human stromelysin complexed with a hydrophobic inhibitor

Solution structure of the catalytic domain of human stromelysin complexed with a hydrophobic inhibitor

The astacin family of metalloendopeptidases

Zinc Complexes of Tripodal N3O Ligands

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