EzCatDB: S00397

DB codeS00397
RLCP classification1.13.13000.460
CATH domainDomain 13.40.390.10Catalytic domain
E.C.3.4.24.34

CATH domainRelated DB codes (homologues)
3.40.390.10S00394,S00395,S00398,S00399,D00232,D00236,M00101

Enzyme Name
Swiss-protKEGG

P22894
Protein nameNeutrophil collagenaseneutrophil collagenase
matrix metalloproteinase 8
PMNL collagenase
MMP-8
SynonymsEC 3.4.24.34
Matrix metalloproteinase-8
MMP-8
PMNL collagenase
PMNL-CL


Swiss-prot:Accession NumberP22894
Entry nameMMP8_HUMAN
ActivityCleavage of interstitial collagens in the triple helical domain. Unlike EC 3.4.24.7, this enzyme cleaves type III collagen more slowly than type I.
Subunit
Subcellular locationCytoplasmic granule. Secreted, extracellular space, extracellular matrix (Probable). Note=Stored in intracellular granules.
CofactorBinds 3 calcium ions per subunit.,Binds 2 zinc ions per subunit.


CofactorsSubstratesProductsintermediates
KEGG-idC00076C00038C00211C00001C00017C00012
CompoundCalciumZincCollagenH2OProteinPeptide
Typedivalent metal (Ca2+, Mg2+)heavy metalamine group,carboxyl group,peptide/proteinH2Opeptide/proteinpeptide/protein
1a85ABound:2x_CABound:2x_ZNUnbound
UnboundUnboundUnbound
1a86ABound:2x_CABound:2x_ZNUnbound
UnboundUnboundUnbound
1bzsABound:2x_CABound:2x_ZNUnbound
UnboundUnboundUnbound
1i73ABound:2x_CABound:2x_ZNUnbound
UnboundAnalogue:PRO-LEU-PATUnbound
1i76ABound:2x_CABound:2x_ZNUnbound
UnboundAnalogue:BSIUnbound
1janABound:2x_CABound:2x_ZNAnalogue:PRO-LEU-GLY-HOA
UnboundUnboundUnbound
1jaoABound:2x_CABound:2x_ZNUnbound
UnboundUnboundUnbound
1japABound:2x_CABound:2x_ZNAnalogue:PRO-LEU-GLY-HOA
UnboundUnboundUnbound
1jaqABound:2x_CABound:2x_ZNUnbound
UnboundUnboundUnbound
1kbcABound:2x_CABound:2x_ZNUnbound
UnboundUnboundUnbound
1kbcBBound:2x_CABound:2x_ZNUnbound
UnboundUnboundUnbound
1mmbABound:2x_CABound:2x_ZNUnbound
UnboundUnboundUnbound
1mncABound:_CABound:2x_ZNUnbound
UnboundUnboundIntermediate-analogue:PLH

Active-site residues
pdbCatalytic residuesCofactor-binding residues
1a85AGLU 198
HIS 197;HIS 201;HIS 207(Zinc binding)
1a86AGLU 198
HIS 197;HIS 201;HIS 207(Zinc binding)
1bzsAGLU 198
HIS 197;HIS 201;HIS 207(Zinc binding)
1i73AGLU 198
HIS 197;HIS 201;HIS 207(Zinc binding)
1i76AGLU 198
HIS 197;HIS 201;HIS 207(Zinc binding)
1janAGLU 198
HIS 197;HIS 201;HIS 207(Zinc binding)
1jaoAGLU 198
HIS 197;HIS 201;HIS 207(Zinc binding)
1japAGLU 198
HIS 197;HIS 201;HIS 207(Zinc binding)
1jaqAGLU 198
HIS 197;HIS 201;HIS 207(Zinc binding)
1kbcAGLU 198
HIS 197;HIS 201;HIS 207(Zinc binding)
1kbcBGLU 198
HIS 197;HIS 201;HIS 207(Zinc binding)
1mmbAGLU 198
HIS 197;HIS 201;HIS 207(Zinc binding)
1mncAGLU 219
HIS 218;HIS 222;HIS 228(Zinc binding)

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[4]p.836-838, Fig.7, Fig.8
[15]p.18663

references
[1]
CommentsX-ray crystallography
Medline ID94139930
PubMed ID8307185
JournalFEBS Lett
Year1994
Volume338
Pages227-33
AuthorsReinemer P, Grams F, Huber R, Kleine T, Schnierer S, Piper M, Tschesche H, Bode W
TitleStructural implications for the role of the N terminus in the 'superactivation' of collagenases. A crystallographic study.
Related PDB1jan
Related Swiss-protP22894
[2]
CommentsX-ray crystallography (2.1 Angstroms)
Medline ID95384762
PubMed ID7656015
JournalNat Struct Biol
Year1994
Volume1
Pages119-23
AuthorsStams T, Spurlino JC, Smith DL, Wahl RC, Ho TF, Qoronfleh MW, Banks TM, Rubin B
TitleStructure of human neutrophil collagenase reveals large S1' specificity pocket.
Related PDB1mnc
Related Swiss-protP22894
[3]
CommentsX-ray crystallography (2.0 Angstroms)
Medline ID94185631
PubMed ID8137810
JournalEMBO J
Year1994
Volume13
Pages1263-9
AuthorsBode W, Reinemer P, Huber R, Kleine T, Schnierer S, Tschesche H
TitleThe X-ray crystal structure of the catalytic domain of human neutrophil collagenase inhibited by a substrate analogue reveals the essentials for catalysis and specificity.
Related PDB1jap
Related Swiss-protP22894
[4]
CommentsX-ray crystallography (2.4/2.25 Angstroms)
PubMed ID7737183
JournalEur J Biochem
Year1995
Volume228
Pages830-41
AuthorsGrams F, Reinemer P, Powers JC, Kleine T, Pieper M, Tschesche H, Huber R, Bode W
TitleX-ray structures of human neutrophil collagenase complexed with peptide hydroxamate and peptide thiol inhibitors. Implications for substrate binding and rational drug design.
Related PDB1jao,1jaq
[5]
PubMed ID7663339
JournalProtein Sci
Year1995
Volume4
Pages823-40
AuthorsStocker W, Grams F, Baumann U, Reinemer P, Gomis-Ruth FX, McKay DB, Bode W
TitleThe metzincins--topological and sequential relations between the astacins, adamalysins, serralysins, and matrixins (collagenases) define a superfamily of zinc-peptidases.
[6]
PubMed ID8590015
JournalStructure
Year1995
Volume3
Pages541-9
AuthorsLi J, Brick P, O'Hare MC, Skarzynski T, Lloyd LF, Curry VA, Clark IM, Bigg HF, Hazleman BL, Cawston TE, et al
TitleStructure of full-length porcine synovial collagenase reveals a C-terminal domain containing a calcium-linked, four-bladed beta-propeller.
[7]
CommentsX-ray crystallography (2.1 Angstroms)
PubMed ID7577999
JournalBiochemistry
Year1995
Volume34
Pages14012-20
AuthorsGrams F, Crimmin M, Hinnes L, Huxley P, Pieper M, Tschesche H, Bode W
TitleStructure determination and analysis of human neutrophil collagenase complexed with a hydroxamate inhibitor.
Related PDB1mmb
[8]
CommentsX-ray crystallography (1.8 Angstroms)
Medline ID97390108
PubMed ID9249047
JournalEur J Biochem
Year1997
Volume247
Pages356-63
AuthorsBetz M, Huxley P, Davies SJ, Mushtaq Y, Pieper M, Tschesche H, Bode W, Gomis-Ruth FX
Title1.8-A crystal structure of the catalytic domain of human neutrophil collagenase (matrix metalloproteinase-8) complexed with a peptidomimetic hydroxamate primed-side inhibitor with a distinct selectivity profile.
Related PDB1kbc
Related Swiss-protP22894
[9]
CommentsX-ray crystallography
Medline ID98318039
PubMed ID9655333
JournalProtein Sci
Year1998
Volume7
Pages1303-9
AuthorsBrandstetter H, Engh RA, Von Roedern EG, Moroder L, Huber R, Bode W, Grams F
TitleStructure of malonic acid-based inhibitors bound to human neutrophil collagenase. A new binding mode explains apparently anomalous data.
Related PDB1a85,1a86
Related Swiss-protP22894
[10]
CommentsX-ray crystallography
PubMed ID9685244
JournalJ Med Chem
Year1998
Volume41
Pages3041-7
AuthorsGraf von Roedern E, Brandstetter H, Engh RA, Bode W, Grams F, Moroder L
TitleBis-substituted malonic acid hydroxamate derivatives as inhibitors of human neutrophil collagenase (MMP8).
[11]
PubMed ID9781680
JournalFEBS Lett
Year1998
Volume436
Pages209-12
AuthorsKrumme D, Wenzel H, Tschesche H
TitleHydroxamate derivatives of substrate-analogous peptides containing aminomalonic acid are potent inhibitors of matrix metalloproteinases.
[12]
PubMed ID10353819
JournalBiochemistry
Year1999
Volume38
Pages7085-96
AuthorsMoy FJ, Chanda PK, Chen JM, Cosmi S, Edris W, Skotnicki JS, Wilhelm J, Powers R
TitleNMR solution structure of the catalytic fragment of human fibroblast collagenase complexed with a sulfonamide derivative of a hydroxamic acid compound.
[13]
PubMed ID10353844
JournalBiochemistry
Year1999
Volume38
Pages7332-8
AuthorsFarr M, Pieper M, Calvete J, Tschesche H
TitleThe N-terminus of collagenase MMP-8 determines superactivity and inhibition: a relation of structure and function analyzed by biomolecular interaction analysis.
[14]
CommentsX-ray crystallography (1.7 Angstroms)
PubMed ID10354399
JournalJ Med Chem
Year1999
Volume42
Pages1908-20
AuthorsMatter H, Schwab W, Barbier D, Billen G, Haase B, Neises B, Schudok M, Thorwart W, Schreuder H, Brachvogel V, Lonze P, Weithmann KU
TitleQuantitative structure-activity relationship of human neutrophil collagenase (MMP-8) inhibitors using comparative molecular field analysis and X-ray structure analysis.
Related PDB1bzs
[15]
PubMed ID10749856
JournalJ Biol Chem
Year2000
Volume275
Pages18657-63
AuthorsMarini S, Fasciglione GF, de Sanctis G, D'Alessio S, Politi V, Coletta M
TitleCleavage of bovine collagen I by neutrophil collagenase MMP-8. Effect of pH on the catalytic properties as compared to synthetic substrates.
[16]
PubMed ID10930399
JournalJ Biol Chem
Year2000
Volume275
Pages33008-13
AuthorsHiller O, Lichte A, Oberpichler A, Kocourek A, Tschesche H
TitleMatrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII.
[17]
Commentscrystal structures using synchrotron radiation
PubMed ID10978185
JournalJ Med Chem
Year2000
Volume43
Pages3377-85
AuthorsGavuzzo E, Pochetti G, Mazza F, Gallina C, Gorini B, D'Alessio S, Pieper M, Tschesche H, Tucker PA
TitleTwo crystal structures of human neutrophil collagenase, one complexed with a primed- and the other with an unprimed-side inhibitor: implications for drug design.
Related PDB1i73,1i76
[18]
PubMed ID11023917
JournalBiophys J
Year2000
Volume79
Pages2138-49
AuthorsFasciglione GF, Marini S, D'Alessio S, Politi V, Coletta M
TitlepH- and temperature-dependence of functional modulation in metalloproteinases. A comparison between neutrophil collagenase and gelatinases A and B.
[19]
CommentsX-ray crystallography (1.8 Angstroms)
PubMed ID11278347
JournalJ Biol Chem
Year2001
Volume276
Pages17405-12
AuthorsBrandstetter H, Grams F, Glitz D, Lang A, Huber R, Bode W, Krell HW, Engh RA
TitleThe 1.8-A crystal structure of a matrix metalloproteinase 8-barbiturate inhibitor complex reveals a previously unobserved mechanism for collagenase substrate recognition.
[20]
PubMed ID11575929
JournalJ Mol Biol
Year2001
Volume312
Pages743-51
AuthorsNar H, Werle K, Bauer MM, Dollinger H, Jung B
TitleCrystal structure of human macrophage elastase (MMP-12) in complex with a hydroxamic acid inhibitor.
[21]
PubMed ID11563922
JournalJ Med Chem
Year2001
Volume44
Pages3231-43
AuthorsSchroder J, Henke A, Wenzel H, Brandstetter H, Stammler HG, Stammler A, Pfeiffer WD, Tschesche H
TitleStructure-based design and synthesis of potent matrix metalloproteinase inhibitors derived from a 6H-1,3,4-thiadiazine scaffold.
[22]
PubMed ID11953425
JournalJ Biol Chem
Year2002
Volume277
Pages23123-30
AuthorsGioia M, Fasciglione GF, Marini S, D'Alessio S, De Sanctis G, Diekmann O, Pieper M, Politi V, Tschesche H, Coletta M
TitleModulation of the catalytic activity of neutrophil collagenase MMP-8 on bovine collagen I. Role of the activation cleavage and of the hemopexin-like domain.
[23]
PubMed ID12011042
JournalJ Biol Chem
Year2002
Volume277
Pages27378-84
AuthorsTsukada H, Pourmotabbed T
TitleUnexpected crucial role of residue 272 in substrate specificity of fibroblast collagenase.

comments
This enzyme belongs to the peptidase family-M10A. Moreover, this enzyme belongs to Matrix metalloproteinases (MMP-8).
According to the literature [4], the catalysis proceeds through the following steps:
(1) the general base (Glu198) catalyzes the nucleophilic attack of a zinc-ligated water molecule on the carbonyl group of the scissile peptide bond.
(2) the carboxy anion of the tetrahedral transition state must be stabilized.
(3) the same residue (Glu198) mediates the transfer of its proton to the leaving amino group, giving rise to the product.
However, another paper [15] suggested the role of Glu198 is still a matter of debate, based on the experimental results of homologous enzyme, matrilysin (MMP-7; see S00395 in EzCatDB).
The pKa of Glu198 must be quite high, due to its hydrophobic environment, which is similar to that of matrilysin (S00395 in EzCatDB), suggesting that the sidechain of this residue must be protonated. Thus, Glu198 is unlikely to act as a general base, in the first place.

createdupdated
2002-08-292009-02-26
Copyright: Nozomi Nagano, JST & CBRC-AIST
Funded by PRESTO/Japan Science and Technology Corporation (JST) (December 2001 - November 2004)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2010)
Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2011 - March 2012)

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