Sandbox Reserved 468: Difference between revisions

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'''Hemopexin-like domain'''

The <scene name='Sandbox_Reserved_468/Linker_region/1'>Hemopexin-like domain</scene> starts with Cys259 and forms a complete circle by joining to Cys447 using a disulfide bond that connects and gives this domain the characteristic four-bladed β-propeller structure. β-Propeller structures provide a large flat surface that is thought to be involved in protein-protein interactions. This determines substrate specificity and is the site for interaction with TIMP’s (tissue inhibitor of metalloproteinases). Each blade starts near the periphery, in which the Asp residues (Asp266, Asp359 and Asp408) coordinate the central calcium ion through their carbonyl oxygen atom. Glu310 provides the fourth coordination thus completing the acidic patch at the entrance of the central, solvent-accessible channel. The side-chains of these residues form salt bridges to the neighbouring β-strands holding the entrance of the central channel together. Three water molecules are found trapped in the center of this channel but these molecules are not involved in this process. Two of the water molecules are at positions corresponding to the sodium and chloride ion in the proMMP-1 structure. The water molecule corresponding to the sodium ion is at hydrogen-bonding distances to the carbonyl oxygen atom of Ile268, Ala312, Ala361 and Val410.

The <scene name='Sandbox_Reserved_468/Linker_region/1'>Hemopexin-like domain</scene> starts with Cys259 and forms a complete circle by joining to Cys447 using a disulfide bond that connects and gives this domain the characteristic four-bladed β-propeller structure. β-Propeller structures provide a large flat surface that is thought to be involved in protein-protein interactions. This determines substrate specificity and is the site for interaction with TIMP’s (tissue inhibitor of metalloproteinases). Each blade starts near the periphery, in which the Asp residues (Asp266, Asp359 and Asp408) coordinate the central calcium ion through their carbonyl oxygen atom. Glu310 provides the fourth coordination thus completing the acidic patch at the entrance of the central, solvent-accessible channel. The side-chains of these residues form salt bridges to the neighbouring β-strands holding the entrance of the central channel together. Three water molecules are found trapped in the center of this channel but these molecules are not involved in this process. Two of the water molecules are at positions corresponding to the sodium and chloride ion in the proMMP-1 structure. The water molecule corresponding to the sodium ion is at hydrogen-bonding distances to the carbonyl oxygen atom of Ile268, Ala312, Ala361 and Val410 [3].

== Mechanism of Action ==

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In the second mechanism, the Matthews-mechanism, Kester and Matthews suggested an interaction between a water molecule and the Zn2+ ion during the acid-base catalysis.

In the third mechanism, the Manzetti-mechanism, Manzetti Sergio and colleagues provided evidence that a coordination between water and zinc during catalysis was unlikely, and suggested a third mechanism wherein a histidine participates in catalysis by allowing the Zn2+ ion to assume a quasi-penta coordinated state, via its dissociation from it. In this state, the Zn2+ ion is coordinated with the two oxygen atoms from the catalytic glutamic acid, the substrate's carbonyl oxygen atom, and the two histidine residues, and can polarize the glutamic acid's oxygen atom, proximate the scissile bond, and induce it to act as reversible electron donor. This forms an oxyanion transition state. At this stage, a water molecule acts on the dissociated scissile bond and completes the hydrolyzation of the substrate.

In the third mechanism, the Manzetti-mechanism, Manzetti Sergio and colleagues provided evidence that a coordination between water and zinc during catalysis was unlikely, and suggested a third mechanism wherein a histidine participates in catalysis by allowing the Zn2+ ion to assume a quasi-penta coordinated state, via its dissociation from it. In this state, the Zn2+ ion is coordinated with the two oxygen atoms from the catalytic glutamic acid, the substrate's carbonyl oxygen atom, and the two histidine residues, and can polarize the glutamic acid's oxygen atom, proximate the scissile bond, and induce it to act as reversible electron donor. This forms an oxyanion transition state. At this stage, a water molecule acts on the dissociated scissile bond and completes the hydrolyzation of the substrate [5][6].

== Medical Implications ==

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@@ Line 31: / Line 31: @@
 '''Hemopexin-like domain'''
-The <scene name='Sandbox_Reserved_468/Linker_region/1'>Hemopexin-like domain</scene> starts with Cys259 and forms a complete circle by joining to Cys447 using a disulfide bond that connects and gives this domain the characteristic four-bladed β-propeller structure. β-Propeller structures provide a large flat surface that is thought to be involved in protein-protein interactions. This determines substrate specificity and is the site for interaction with TIMP’s (tissue inhibitor of metalloproteinases). Each blade starts near the periphery, in which the Asp residues (Asp266, Asp359 and Asp408) coordinate the central calcium ion through their carbonyl oxygen atom. Glu310 provides the fourth coordination thus completing the acidic patch at the entrance of the central, solvent-accessible channel. The side-chains of these residues form salt bridges to the neighbouring β-strands holding the entrance of the central channel together. Three water molecules are found trapped in the center of this channel but these molecules are not involved in this process. Two of the water molecules are at positions corresponding to the sodium and chloride ion in the proMMP-1 structure. The water molecule corresponding to the sodium ion is at hydrogen-bonding distances to the carbonyl oxygen atom of Ile268, Ala312, Ala361 and Val410.
+The <scene name='Sandbox_Reserved_468/Linker_region/1'>Hemopexin-like domain</scene> starts with Cys259 and forms a complete circle by joining to Cys447 using a disulfide bond that connects and gives this domain the characteristic four-bladed β-propeller structure. β-Propeller structures provide a large flat surface that is thought to be involved in protein-protein interactions. This determines substrate specificity and is the site for interaction with TIMP’s (tissue inhibitor of metalloproteinases). Each blade starts near the periphery, in which the Asp residues (Asp266, Asp359 and Asp408) coordinate the central calcium ion through their carbonyl oxygen atom. Glu310 provides the fourth coordination thus completing the acidic patch at the entrance of the central, solvent-accessible channel. The side-chains of these residues form salt bridges to the neighbouring β-strands holding the entrance of the central channel together. Three water molecules are found trapped in the center of this channel but these molecules are not involved in this process. Two of the water molecules are at positions corresponding to the sodium and chloride ion in the proMMP-1 structure. The water molecule corresponding to the sodium ion is at hydrogen-bonding distances to the carbonyl oxygen atom of Ile268, Ala312, Ala361 and Val410 [3].
 == Mechanism of Action ==
@@ Line 41: / Line 41: @@
 In the second mechanism, the Matthews-mechanism, Kester and Matthews suggested an interaction between a water molecule and the Zn2+ ion during the acid-base catalysis.
-In the third mechanism, the Manzetti-mechanism, Manzetti Sergio and colleagues provided evidence that a coordination between water and zinc during catalysis was unlikely, and suggested a third mechanism wherein a histidine participates in catalysis by allowing the Zn2+ ion to assume a quasi-penta coordinated state, via its dissociation from it. In this state, the Zn2+ ion is coordinated with the two oxygen atoms from the catalytic glutamic acid, the substrate's carbonyl oxygen atom, and the two histidine residues, and can polarize the glutamic acid's oxygen atom, proximate the scissile bond, and induce it to act as reversible electron donor. This forms an oxyanion transition state. At this stage, a water molecule acts on the dissociated scissile bond and completes the hydrolyzation of the substrate.
+In the third mechanism, the Manzetti-mechanism, Manzetti Sergio and colleagues provided evidence that a coordination between water and zinc during catalysis was unlikely, and suggested a third mechanism wherein a histidine participates in catalysis by allowing the Zn2+ ion to assume a quasi-penta coordinated state, via its dissociation from it. In this state, the Zn2+ ion is coordinated with the two oxygen atoms from the catalytic glutamic acid, the substrate's carbonyl oxygen atom, and the two histidine residues, and can polarize the glutamic acid's oxygen atom, proximate the scissile bond, and induce it to act as reversible electron donor. This forms an oxyanion transition state. At this stage, a water molecule acts on the dissociated scissile bond and completes the hydrolyzation of the substrate [5][6].
 == Medical Implications ==