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Insight towards the conserved water mediated recognition of catalytic and structural Zn(+2) ions in human Matrix Metalloproteinase-8 enzyme: A study by MD-simulation methods.

Chakrabarti B, Bairagya HR, Mishra DK, Chatterjee PK, Mukhopadhyay BP - Bioinformation (2013)

Bottom Line: The coordination of two conserved water molecules (W and WS) to ZnS and the H-bonding interaction of WS to S151 have indicated the plausible involvement of that metal ion in the catalytic process.Beside this the coupling of ZnC and ZnS metal ions (ZnC - W(H) (W(1))…..W(2) ….H(162) - ZnS) through two conserved hydrophilic centers (occupied by water molecules) may also provide some rational on the recognition of two zinc ions which were separated by ~13 Å in their X-ray structures.This unique recognition of both the Zn(+2) ions in the enzyme through conserved water molecules may be implemented/ exploited for the design of antiproteolytic agent using water mimic drug design protocol.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, National Institute of Technology, Durgapur - 713 209, W.B. India.

ABSTRACT
Human matrix metalloproteinase-8 (hMMP-8) plays a important role in the progression of colorectal cancer, metastasis, multiple sclerosis and rheumetoid arthritis. Extensive MD-simulation of the PDB and solvated structures of hMMP-8 has revealed the presence of few conserved water molecules around the catalytic and structural zinc (ZnC and ZnS) ions. The coordination of two conserved water molecules (W and WS) to ZnS and the H-bonding interaction of WS to S151 have indicated the plausible involvement of that metal ion in the catalytic process. Beside this the coupling of ZnC and ZnS metal ions (ZnC - W(H) (W(1))…..W(2) ….H(162) - ZnS) through two conserved hydrophilic centers (occupied by water molecules) may also provide some rational on the recognition of two zinc ions which were separated by ~13 Å in their X-ray structures. This unique recognition of both the Zn(+2) ions in the enzyme through conserved water molecules may be implemented/ exploited for the design of antiproteolytic agent using water mimic drug design protocol.

No MeSH data available.


Related in: MedlinePlus

Proposed mechanism on water mediate hydrolysis of substrate in hMMP-8.
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Figure 3: Proposed mechanism on water mediate hydrolysis of substrate in hMMP-8.

Mentions: The variation of coordination geometry from tetrahedral todistorted octahedral through the interaction of two watermolecule (W and WS) directly to ZnS in all the PDB and solvatedMD–simulated structures and the H–bonding of WS withS151(OG) Table 7 (see supplementary material) indicated thepossible involvement of metal ion and S151 to the catalyticprocess. Furthermore, the recognition of the ZnC and ZnS(which are ~ 13Å apart) through two conserved watermolecules (WH / W1 and W2) and the observation of similartype of water mediated conjugation of metal ions in differentsynthetic Zn–complexes [29,30] may also support the role oftwo Zn centres in the function and mechanism of enzyme(Figure 2 … Figure 3). Based on the dynamical results of this work theparticipation of ZnS in the collagenolysis mechanism of hMMP-8 may be proposed (Figure 3). The ZnS directly binds tosubstrate and polarize it and subsequently activate the watermolecule which may then act as a nucleophile. The ZnS boundWS (water molecule) and S151(OG) may also thought to activatethe metal ion in the intermediate transition steeps of thephotolytic mechanism.


Insight towards the conserved water mediated recognition of catalytic and structural Zn(+2) ions in human Matrix Metalloproteinase-8 enzyme: A study by MD-simulation methods.

Chakrabarti B, Bairagya HR, Mishra DK, Chatterjee PK, Mukhopadhyay BP - Bioinformation (2013)

Proposed mechanism on water mediate hydrolysis of substrate in hMMP-8.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3569599&req=5

Figure 3: Proposed mechanism on water mediate hydrolysis of substrate in hMMP-8.
Mentions: The variation of coordination geometry from tetrahedral todistorted octahedral through the interaction of two watermolecule (W and WS) directly to ZnS in all the PDB and solvatedMD–simulated structures and the H–bonding of WS withS151(OG) Table 7 (see supplementary material) indicated thepossible involvement of metal ion and S151 to the catalyticprocess. Furthermore, the recognition of the ZnC and ZnS(which are ~ 13Å apart) through two conserved watermolecules (WH / W1 and W2) and the observation of similartype of water mediated conjugation of metal ions in differentsynthetic Zn–complexes [29,30] may also support the role oftwo Zn centres in the function and mechanism of enzyme(Figure 2 … Figure 3). Based on the dynamical results of this work theparticipation of ZnS in the collagenolysis mechanism of hMMP-8 may be proposed (Figure 3). The ZnS directly binds tosubstrate and polarize it and subsequently activate the watermolecule which may then act as a nucleophile. The ZnS boundWS (water molecule) and S151(OG) may also thought to activatethe metal ion in the intermediate transition steeps of thephotolytic mechanism.

Bottom Line: The coordination of two conserved water molecules (W and WS) to ZnS and the H-bonding interaction of WS to S151 have indicated the plausible involvement of that metal ion in the catalytic process.Beside this the coupling of ZnC and ZnS metal ions (ZnC - W(H) (W(1))…..W(2) ….H(162) - ZnS) through two conserved hydrophilic centers (occupied by water molecules) may also provide some rational on the recognition of two zinc ions which were separated by ~13 Å in their X-ray structures.This unique recognition of both the Zn(+2) ions in the enzyme through conserved water molecules may be implemented/ exploited for the design of antiproteolytic agent using water mimic drug design protocol.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, National Institute of Technology, Durgapur - 713 209, W.B. India.

ABSTRACT
Human matrix metalloproteinase-8 (hMMP-8) plays a important role in the progression of colorectal cancer, metastasis, multiple sclerosis and rheumetoid arthritis. Extensive MD-simulation of the PDB and solvated structures of hMMP-8 has revealed the presence of few conserved water molecules around the catalytic and structural zinc (ZnC and ZnS) ions. The coordination of two conserved water molecules (W and WS) to ZnS and the H-bonding interaction of WS to S151 have indicated the plausible involvement of that metal ion in the catalytic process. Beside this the coupling of ZnC and ZnS metal ions (ZnC - W(H) (W(1))…..W(2) ….H(162) - ZnS) through two conserved hydrophilic centers (occupied by water molecules) may also provide some rational on the recognition of two zinc ions which were separated by ~13 Å in their X-ray structures. This unique recognition of both the Zn(+2) ions in the enzyme through conserved water molecules may be implemented/ exploited for the design of antiproteolytic agent using water mimic drug design protocol.

No MeSH data available.


Related in: MedlinePlus