X-RAY STRUCTURES OF HUMAN NEUTROPHIL COLLAGENASE COMPLEXED WITH PEPTIDE HYDROXAMATE AND PEPTIDE THIOL INHIBITORS - IMPLICATIONS FOR SUBSTRATE-BINDING AND RATIONAL DRUG DESIGN

GRAMS F, REINEMER P, POWERS JC, KLEINE T, PIEPER M, Tschesche H, HUBER R, BODE W (1995)
EUROPEAN JOURNAL OF BIOCHEMISTRY 228(3): 830-841.

Download
Es wurde kein Volltext hochgeladen. Nur Publikationsnachweis!
Zeitschriftenaufsatz | Veröffentlicht | Englisch
Autor
; ; ; ; ; ; ;
Abstract / Bemerkung
Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases involved in tissue remodeling. They have also been implicated in various disease processes including tumour invasion and joint destruction and are therefore attractive targets for inhibitor design. For rational drug design, information of inhibitor binding at the atomic level is essential. Recently, we have published the refined high-resolution crystal structure of the catalytic domain of human neutrophil collagenase (HNC) complexed with the inhibitor Pro-Leu-Gly-NHOH, which is a mimic for the unprimed (P3-P1) residues of a bound peptide substrate. We have now determined two additional HNC complexes formed with the thiol inhibitor HSCH2CH(CH(2)Ph)CO-L-Ala-Gly-NH2 and another hydroxamate inhibitor, HONHCOCH(iBu)CO-L-Ala-Gly-NH2,, which were both refined to R-values of 0.183/0.198 at 0.240/0.225-nm resolution. The inhibitor thiol and hydroxamate groups ligand the catalytic zinc, giving rise to a slightly distorted tetrahedral and trigonal-bipyramidal coordination sphere, respectively. The thiol inhibitor diastereomer with S-configuration at the P1' residue (corresponding to an L-amino acid analog) binds to HNC. Its peptidyl moiety mimics binding of primed (P1'-P3') residues of the substrate. In combination with our first structure a continuous hexapeptide corresponding to a peptide substrate productively bound to HNC was constructed and energy-minimized. Proteolytic cleavage of this Michaelis complex is probably general base-catalyzed as proposed for thermolysin, i.e. a glutamate assists nucleophilic attack of a water molecule. Although there are many structural and mechanistic similarities to thermolysin, substrate binding to MMPs differs due to the interactions beyond S1'-P1' While thermolysin binds substrates with a kink at P1', substrates are bound in an extended conformation in the collagenases. This property explains the tolerance of thermolysin for D-amino acid residues at the P1' position, in contrast to the collagenases. The third inhibitor, HONHCOCH(iBu)CO-L-Ala-Gly-NH2, unexpectedly binds in a different manner than anticipated from its design and binding mode in thermolysin. Its hydroxamate group obviously interacts with the catalytic zinc in a favourable bidentate manner, but in contrast its isobutyl (iBu) side chain remains outside of the S1' pocket, presumably due to severe constraints imposed by the adjacent planar hydroxamate group. Instead, the C-terminal Ala-Gly-NH2 tail adopts a bent conformation and inserts into this S1' pocket, presumably in a non-optimized manner. Both the isobutyl side chain and the C-terminal peptide tail could be replaced by other, better fitting groups. Thus this inhibitor seems to represent a new lead structure suitable for designing better drugs.
Erscheinungsjahr
Zeitschriftentitel
EUROPEAN JOURNAL OF BIOCHEMISTRY
Band
228
Zeitschriftennummer
3
Seite
830-841
ISSN
eISSN
PUB-ID

Zitieren

GRAMS F, REINEMER P, POWERS JC, et al. X-RAY STRUCTURES OF HUMAN NEUTROPHIL COLLAGENASE COMPLEXED WITH PEPTIDE HYDROXAMATE AND PEPTIDE THIOL INHIBITORS - IMPLICATIONS FOR SUBSTRATE-BINDING AND RATIONAL DRUG DESIGN. EUROPEAN JOURNAL OF BIOCHEMISTRY. 1995;228(3):830-841.
GRAMS, F., REINEMER, P., POWERS, J. C., KLEINE, T., PIEPER, M., Tschesche, H., HUBER, R., et al. (1995). X-RAY STRUCTURES OF HUMAN NEUTROPHIL COLLAGENASE COMPLEXED WITH PEPTIDE HYDROXAMATE AND PEPTIDE THIOL INHIBITORS - IMPLICATIONS FOR SUBSTRATE-BINDING AND RATIONAL DRUG DESIGN. EUROPEAN JOURNAL OF BIOCHEMISTRY, 228(3), 830-841. doi:10.1111/j.1432-1033.1995.tb20329.x
GRAMS, F., REINEMER, P., POWERS, J. C., KLEINE, T., PIEPER, M., Tschesche, H., HUBER, R., and BODE, W. (1995). X-RAY STRUCTURES OF HUMAN NEUTROPHIL COLLAGENASE COMPLEXED WITH PEPTIDE HYDROXAMATE AND PEPTIDE THIOL INHIBITORS - IMPLICATIONS FOR SUBSTRATE-BINDING AND RATIONAL DRUG DESIGN. EUROPEAN JOURNAL OF BIOCHEMISTRY 228, 830-841.
GRAMS, F., et al., 1995. X-RAY STRUCTURES OF HUMAN NEUTROPHIL COLLAGENASE COMPLEXED WITH PEPTIDE HYDROXAMATE AND PEPTIDE THIOL INHIBITORS - IMPLICATIONS FOR SUBSTRATE-BINDING AND RATIONAL DRUG DESIGN. EUROPEAN JOURNAL OF BIOCHEMISTRY, 228(3), p 830-841.
F. GRAMS, et al., “X-RAY STRUCTURES OF HUMAN NEUTROPHIL COLLAGENASE COMPLEXED WITH PEPTIDE HYDROXAMATE AND PEPTIDE THIOL INHIBITORS - IMPLICATIONS FOR SUBSTRATE-BINDING AND RATIONAL DRUG DESIGN”, EUROPEAN JOURNAL OF BIOCHEMISTRY, vol. 228, 1995, pp. 830-841.
GRAMS, F., REINEMER, P., POWERS, J.C., KLEINE, T., PIEPER, M., Tschesche, H., HUBER, R., BODE, W.: X-RAY STRUCTURES OF HUMAN NEUTROPHIL COLLAGENASE COMPLEXED WITH PEPTIDE HYDROXAMATE AND PEPTIDE THIOL INHIBITORS - IMPLICATIONS FOR SUBSTRATE-BINDING AND RATIONAL DRUG DESIGN. EUROPEAN JOURNAL OF BIOCHEMISTRY. 228, 830-841 (1995).
GRAMS, F, REINEMER, P, POWERS, JC, KLEINE, T, PIEPER, M, Tschesche, Harald, HUBER, R, and BODE, W. “X-RAY STRUCTURES OF HUMAN NEUTROPHIL COLLAGENASE COMPLEXED WITH PEPTIDE HYDROXAMATE AND PEPTIDE THIOL INHIBITORS - IMPLICATIONS FOR SUBSTRATE-BINDING AND RATIONAL DRUG DESIGN”. EUROPEAN JOURNAL OF BIOCHEMISTRY 228.3 (1995): 830-841.

73 Zitationen in Europe PMC

Daten bereitgestellt von Europe PubMed Central.

Phosphonate inhibitors of adamalysin II and matrix metalloproteinases.
Gallina C, Gavuzzo E, Giordano C, Gorini B, Mazza F, Paglialunga-Paradisi M, Panini G, Pochetti G, Politi V., Ann N Y Acad Sci 878(), 1999
PMID: 10415812
The synthesis and biological evaluation of non-peptidic matrix metalloproteinase inhibitors.
Martin FM, Beckett RP, Bellamy CL, Courtney PF, Davies SJ, Drummond AH, Dodd R, Pratt LM, Patel SR, Ricketts ML, Todd RS, Tuffnell AR, Ward JW, Whittaker M., Bioorg Med Chem Lett 9(19), 1999
PMID: 10522712
Conformational homogeneity in molecular recognition by proteolytic enzymes.
Tyndall JD, Fairlie DP., J Mol Recognit 12(6), 1999
PMID: 10611646
Matrix metalloproteases: variations on a theme.
Borkakoti N., Prog Biophys Mol Biol 70(1), 1998
PMID: 9785958
Crystal structure of the catalytic domain of human tumor necrosis factor-alpha-converting enzyme.
Maskos K, Fernandez-Catalan C, Huber R, Bourenkov GP, Bartunik H, Ellestad GA, Reddy P, Wolfson MF, Rauch CT, Castner BJ, Davis R, Clarke HR, Petersen M, Fitzner JN, Cerretti DP, March CJ, Paxton RJ, Black RA, Bode W., Proc Natl Acad Sci U S A 95(7), 1998
PMID: 9520379
Structure of malonic acid-based inhibitors bound to human neutrophil collagenase. A new binding mode explains apparently anomalous data.
Brandstetter H, Engh RA, Von Roedern EG, Moroder L, Huber R, Bode W, Grams F., Protein Sci 7(6), 1998
PMID: 9655333
The crystal structure of the Leishmania major surface proteinase leishmanolysin (gp63).
Schlagenhauf E, Etges R, Metcalf P., Structure 6(8), 1998
PMID: 9739094
Analysis of zinc binding sites in protein crystal structures.
Alberts IL, Nadassy K, Wodak SJ., Protein Sci 7(8), 1998
PMID: 10082367
2 angstrom X-ray structure of adamalysin II complexed with a peptide phosphonate inhibitor adopting a retro-binding mode.
Cirilli M, Gallina C, Gavuzzo E, Giordano C, Gomis-Rüth FX, Gorini B, Kress LF, Mazza F, Paradisi MP, Pochetti G, Politi V., FEBS Lett 418(3), 1997
PMID: 9428736
Non-peptidic cysteine derivatives as inhibitors of matrix metalloproteinases.
Müller JC, von Roedern EG, Grams F, Nagase H, Moroder L., Biol Chem 378(12), 1997
PMID: 9461346
Collagenase: a key enzyme in collagen turnover.
Shingleton WD, Hodges DJ, Brick P, Cawston TE., Biochem Cell Biol 74(6), 1996
PMID: 9164646
A structure-based catalytic mechanism for the xanthine oxidase family of molybdenum enzymes.
Huber R, Hof P, Duarte RO, Moura JJ, Moura I, Liu MY, LeGall J, Hille R, Archer M, Romão MJ., Proc Natl Acad Sci U S A 93(17), 1996
PMID: 8799115
Structural features of a superfamily of zinc-endopeptidases: the metzincins.
Stöcker W, Bode W., Curr Opin Struct Biol 5(3), 1995
PMID: 7583637

52 References

Daten bereitgestellt von Europe PubMed Central.

The Protein Data Bank: a computer-based archival file for macromolecular structures.
Bernstein FC, Koetzle TF, Williams GJ, Meyer EF Jr, Brice MD, Rodgers JR, Kennard O, Shimanouchi T, Tasumi M., J. Mol. Biol. 112(3), 1977
PMID: 875032
Collagenase Inhibitors: Their Design and Potential Therapeutic Use
Johnson, Journal of Enzyme Inhibition and Medicinal Chemistry 2(1), 1987

Export

Markieren/ Markierung löschen
Markierte Publikationen

Open Data PUB

Web of Science

Dieser Datensatz im Web of Science®

Quellen

PMID: 7737183
PubMed | Europe PMC

Suchen in

Google Scholar