Structure of full-length porcine synovial collagenase reveals a C-terminal domain containing a calcium-linked, four-bladed β-propeller

Li, J; Brick, P.; O'Hare, MC; Skarżyński, T.; Lloyd, Lesley F.; Curry, VA; Clark, IM; Bigg, Heather F.; Hazleman, B L; Cawston, TE; Dm, Blow

doi:10.1016/s0969-2126(01)00188-5

Cited by 266 publications

(251 citation statements)

References 39 publications

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“…Even so, the estimates of its secondary structure as determined by C.D. (high fl-sheet and negligible a-helix content) are only partly in accord with the recently published crystal structures of porcine fibroblast collagenase [23] and a deletion mutant of human prostromelysin 1 [24]. The C-terminal domain of collagenase is predominantly fl-sheet but both structures have regions of a-helix in their catalytic domains that are made up of sequences similar to those found in human gelatinase A.…”

Section: Discussionmentioning

confidence: 78%

An analysis of the conformational changes that accompany the activation and inhibition of gelatinase A

Crabbe¹,

Kelly

Price

1996

FEBS Letters

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The latent precursors of the matrix metalloproteinases (MMPs) are converted by (4-aminophenylmercuric)acetate to active forms that lose their propeptide as a result of autolysis. C.D. and an active site mutant of progelatinase A (MMP2) were used to demonstrate that, although propeptide removal is accompanied by a decrease in the enzyme's /]-sheet content, the initial activation is achieved with only minor modifications to the conformation. Mixing activated gelatinase A with the natural inhibitor, TIMP-1, resulted in conformational changes that were absent when a synthetic inhibitor was used. The relevance of these results to MMP activation and inhibition is discussed.

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Section: Discussionmentioning

confidence: 78%

An analysis of the conformational changes that accompany the activation and inhibition of gelatinase A

Crabbe¹,

Kelly

Price

1996

FEBS Letters

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“…The structure was solved by Patterson search methods using the coordinates of the CTD of full-length porcine MMP1 [23] All subsequent refinement steps were performed with X-PLOR [27]. The rigid-body refinement was repeated, allowing an independent All rights reserved.…”

Section: Methodsmentioning

confidence: 99%

“…By comparing it to the recently obtained structure of the MMP-1 CTD [23], we make predictions concerning possible sites of interaction for TIMP-2.…”

Section: Introductionmentioning

confidence: 99%

The C‐terminal (haemopexin‐like) domain structure of human gelatinase A (MMP2): structural implications for its function

Gohlke

Gomis-Rüth

Crabbe³

et al. 1996

FEBS Letters

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In common with most other matrix metalloproteinases, gelatinase A has a non-catalytic C-terminal domain that displays sequence homology to haemopexin. Crystals of this domain were used by molecular replacement to solve its molecular structure at 2.6 A resolution, which was refined to an R value of 17.9%. This structure has a discqike shape, with the chain folded into a/3-propeller structure that has pseudo four-fold symmetry. Although the topology and the side-chain arrangement are very similar to the equivalent domain of fibroblast collagenase, significant differences in surface charge and contouring are observable on 1 side of the gelatinase A disc. This difference might be a factor in allowing the gelatinase A C-terminal domain to bind to natural inhibitor TIMP-2.

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“…In efforts to aid drug design, crystallographic structures of the catalytic domain of fibroblast collagenase or MMP-1 (Borkakoti et al, 1994;Lovejoy et al, 1994aLovejoy et al, , 1994b and of neutrophil collagenase or MMP-8 Reinemer et al, 1994;Stams et al, 1994) have become available. The structure of full-length porcine MMP-I shows that the C-terminal hemopexin-like domain is a four-bladed ''0 propeller" (Li et al, 1995). An NMR solution structure of stromelysin catalytic domain at pH 5.5 complexed with an N-carboxy alkyl inhibitor, N-(R-carboxy-ethyl)-a-(S)-(2-phenyl ethyl)-glycyl-Larginine-N-phenyl amide, has been published as well (Gooley et al, 1994), and has since been further refined (Protein Data Bank access code 2SRT).…”

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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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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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Structure of full-length porcine synovial collagenase reveals a C-terminal domain containing a calcium-linked, four-bladed β-propeller

Cited by 266 publications

References 39 publications

An analysis of the conformational changes that accompany the activation and inhibition of gelatinase A

An analysis of the conformational changes that accompany the activation and inhibition of gelatinase A

The C‐terminal (haemopexin‐like) domain structure of human gelatinase A (MMP2): structural implications for its function

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

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