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Catalytic Site Atlas

CSA LITERATURE entry for 1qrz

E.C. nameplasmin
SpeciesHomo sapiens (Human)
E.C. Number (IntEnz) 3.4.21.7
CSA Homologues of 1qrzThere are 1196 Homologs
CSA Entries With UniProtID P00747
CSA Entries With EC Number 3.4.21.7
PDBe Entry 1qrz
PDBSum Entry 1qrz
MACiE Entry 1qrz

Literature Report

IntroductionPlasmin is a serine protease which is involved in the removal of fibrin from the blood: it is able to catalyse the hydrolysis of the peptide bonds between amino acids in fibrin in order to replace the insoluble protein with soluble amino acids. This results in the breakdown of clots. As a result, plasmin deficiency is associated with increased clotting which can cause diseases such as heart disease and stroke. It displays significant homology, both structural and sequence-wise, to the classic serine proteases chymotrypsin, trypsin and elastin, with the characteristic ser-his-asp triad being prominent. The PDB code 1qrz refers to the inactive precursor plasminogen, which is activated by cleavage leading to the opening of the active site. The specificity pocket is similar to that of trypsin, with plasmin showing a preference for cleavage after aliphatic basic residues such as Lysine and Arginine.
MechansimThe reaction proceeds by initial nucleophilic attack on the peptide bond by Ser 741, activated by deprotonation by His 603. This leads to the formation of a tetrahedral intermediate, stabilised by Ser 741 and Gly 742. Subsequent collapse of this intermediate, assisted by protonation of the leaving group by His 603 and Asp 646 leads to an acyl enzyme intermediate. Activation of a water molecule by His 603 and Asp 646 allows this intermediate to by hydrolysed, resulting in the reformation of the catalytically active Serine residue and the release of the product.
Reaction

Catalytic Sites for 1qrz

Annotated By Reference To The Literature - Site 9 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
HisA603622macie:sideChainActivates Ser 741 to allow it to act as a nucleophile. Then protonates the leaving group to allow collapse of the tetrahedral intermediate. Finally activates water to allow it to hydrolyse the acyl enzyme intermediate.
SerA741760macie:sideChainActs as nucleophile to attack peptide bond and form tetrahedral intermediate, which is stabilised by contacts with the oxyanion hole, which the NH group of the Serine residue contributes to.
SerA741760macie:mainChainAmideActs as nucleophile to attack peptide bond and form tetrahedral intermediate, which is stabilised by contacts with the oxyanion hole, which the NH group of the Serine residue contributes to.
AspA646665macie:sideChainModifies the pKa of His 603 so that it is able to act as an acid-base at physiological pH.
GlyA742761macie:mainChainAmideStabilises the tetrahedral intermediate through contacts with the oxyanion.

Annotated By Reference To The Literature - Site 10 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
HisB603622macie:sideChainActivates Ser 741 to allow it to act as a nucleophile. Then protonates the leaving group to allow collapse of the tetrahedral intermediate. Finally activates water to allow it to hydrolyse the acyl enzyme intermediate.
SerB741760macie:sideChainActs as nucleophile to attack peptide bond and form tetrahedral intermediate, which is stabilised by contacts with the oxyanion hole, which the NH group of the Serine residue contributes to.
SerB741760macie:mainChainAmideActs as nucleophile to attack peptide bond and form tetrahedral intermediate, which is stabilised by contacts with the oxyanion hole, which the NH group of the Serine residue contributes to.
AspB646665macie:sideChainModifies the pKa of His 603 so that it is able to act as an acid-base at physiological pH.
GlyB742761macie:mainChainAmideStabilises the tetrahedral intermediate through contacts with the oxyanion.

Annotated By Reference To The Literature - Site 11 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
HisC603622macie:sideChainActivates Ser 741 to allow it to act as a nucleophile. Then protonates the leaving group to allow collapse of the tetrahedral intermediate. Finally activates water to allow it to hydrolyse the acyl enzyme intermediate.
SerC741760macie:sideChainActs as nucleophile to attack peptide bond and form tetrahedral intermediate, which is stabilised by contacts with the oxyanion hole, which the NH group of the Serine residue contributes to.
SerC741760macie:mainChainAmideActs as nucleophile to attack peptide bond and form tetrahedral intermediate, which is stabilised by contacts with the oxyanion hole, which the NH group of the Serine residue contributes to.
AspC646665macie:sideChainModifies the pKa of His 603 so that it is able to act as an acid-base at physiological pH.
GlyC742761macie:mainChainAmideStabilises the tetrahedral intermediate through contacts with the oxyanion.

Annotated By Reference To The Literature - Site 12 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
HisD603622macie:sideChainActivates Ser 741 to allow it to act as a nucleophile. Then protonates the leaving group to allow collapse of the tetrahedral intermediate. Finally activates water to allow it to hydrolyse the acyl enzyme intermediate.
SerD741760macie:sideChainActs as nucleophile to attack peptide bond and form tetrahedral intermediate, which is stabilised by contacts with the oxyanion hole, which the NH group of the Serine residue contributes to.
SerD741760macie:mainChainAmideActs as nucleophile to attack peptide bond and form tetrahedral intermediate, which is stabilised by contacts with the oxyanion hole, which the NH group of the Serine residue contributes to.
AspD646665macie:sideChainModifies the pKa of His 603 so that it is able to act as an acid-base at physiological pH.
GlyD742761macie:mainChainAmideStabilises the tetrahedral intermediate through contacts with the oxyanion.

Literature References

Notes:
Peisach E
Crystal structure of the proenzyme domain of plasminogen.
Biochemistry 1999 38 11180-11188
PubMed: 10460175
Parry MA.
The ternary microplasmin-staphylokinase-microplasmin complex is a proteinase-cofactor-substrate complex in action
Nat Struct Biol 1998 5 917-923
PubMed: 9783753
Jespers L.
Guiding a docking mode by phage display: selection of correlated mutations at the staphylokinase-plasmin interface
J Mol Biol 1999 290 471-479
PubMed: 10390345
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