PDBsum entry: 1eub

Hydrolase/hydrolase inhibitor

PDB id: 1eub

Contents

Protein chain

171 a.a. *

Ligands

HAV-3MP-MSB

Metals

_ZN ×2

_CA ×2

* Residue conservation analysis

PDB id:

1eub

Name:

Hydrolase/hydrolase inhibitor

Title:

Solution structure of the catalytic domain of human collagenase-3 (mmp-13) complexed to a potent non-peptidic sulfonamide inhibitor

Structure:

Collagenase 3. Chain: a. Fragment: catalytic domain. Synonym: matrix metalloproteinase-13, mmp-13. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.

NMR struc:

20 models

Authors:

X.Zhang,N.C.Gonnella,J.Koehn,N.Pathak,V.Ganu,R.Melton, D.Parker,S.I.Hu,K.Y.Nam

Key ref:

X.Zhang et al. (2000). Solution structure of the catalytic domain of human collagenase-3 (MMP-13) complexed to a potent non-peptidic sulfonamide inhibitor: binding comparison with stromelysin-1 and collagenase-1. J Mol Biol, 301, 513-524. PubMed id: 10926524 DOI: 10.1006/jmbi.2000.3988

Date:

14-Apr-00 Release date: 14-Apr-01

Protein chain

P45452  (MMP13_HUMAN) -  Collagenase 3

Seq: 471 a.a.

Struc: 171 a.a.

 Gene Ontology (GO) functional annotation 

• Cellular component: extracellular matrix (1 term)
• Biological process: proteolysis (1 term)
• Biochemical function: metallopeptidase activity (3 terms)

DOI no: 10.1006/jmbi.2000.3988

J Mol Biol 301:513-524 (2000)

PubMed id: 10926524

Solution structure of the catalytic domain of human collagenase-3 (MMP-13) complexed to a potent non-peptidic sulfonamide inhibitor: binding comparison with stromelysin-1 and collagenase-1.

X.Zhang, N.C.Gonnella, J.Koehn, N.Pathak, V.Ganu, R.Melton, D.Parker, S.I.Hu, K.Y.Nam.

ABSTRACT

The full three-dimensional structure of the catalytic domain of human collagenase-3 (MMP-13) complexed to a potent, sulfonamide hydroxamic acid inhibitor (CGS 27023) has been determined by NMR spectroscopy. The results reveal a core domain for the protein consisting of three alpha-helices and five beta-sheet strands with an overall tertiary fold similar to the catalytic domains of other matrix metalloproteinase family members. The S1' pocket, which is the major site of hydrophobic binding interaction, was found to be a wide cleft spanning the length of the protein and presenting facile opportunity for inhibitor extension deep into the pocket. Comparison with the reported X-ray structure of collagenase-3 showed evidence of flexibility for the loop region flanking the S1' pocket in both NMR and X-ray data. This flexibility was corroborated by NMR dynamics studies. Inhibitor binding placed the methoxy phenyl ring in the S1' pocket with the remainder of the molecule primarily solvent-exposed. The binding mode for this inhibitor was found to be similar with respect to stromelysin-1 and collagenase-1; however, subtle comparative differences in the interactions between inhibitor and enzyme were observed for the three MMPs that were consistent with their respective binding potencies.

Selected figure(s)

Figure 3.
Figure 3. Full 3D structure of the catalytic domain of human collagenase-3 complexed to CGS 27023. The enzyme backbone is shown in blue, antiparallel strand b4 in yellow and the inhibitor is shown in red. Zinc and calcium atoms appear as purple and gray spheres, respectively. Bi-dentate coordination with the catalytic zinc and hydrogen bonding interactions between the inhibitor's sulfonamide oxygen atoms and Leu185 [HN] and the inhibitor's 1HN and the carbonyl oxygen atom of Ala186 are displayed as white dotted lines. The relative orientation of S1' (extending into the plane of the page), S2' and S (opposite direction to S1') are displayed. The phenyl ring (pink) from Tyr214 forms a favorable perpendicular interaction with methoxy phenyl ring of the inhibitor.

Figure 5.
Figure 5. Active site of the collagenase-3-CGS 27023 complex. The inhibitor is displayed as a liquorice model. The NOEs defining the eclipsed orientation of the inhibitor's isopropyl group with its pyridine ring are shown as yellow dotted lines. The enzyme solid surface, generated with the GRASP program [Nicholls et al 1991], shows positive and negative charged surfaces as blue and red patches, respectively.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2000, 301, 513-524) copyright 2000.

Figures were selected by an automated process.