Catalytic Site Atlas
LITERATURE entry for 1bzc
|Species||Homo sapiens (Human)|
E.C. Number (IntEnz)
|CSA Homologues of 1bzc||There are 183 Homologs
CSA Entries With UniProtID
CSA Entries With EC Number
|MACiE Entry ||1bzc|
|Introduction||Protein tyrosine phosphatases catalyse the removal of phosphoryl groups from tyrosine residues in proteins. They play important roles in the control of biological processes such as cell cycles and signal transduction pathways.|
|Mechansim||The reaction occurs via a double displacement mechanism. First, Cys 215 acts as a nucleophile to attack the phosphate of the phosphotyrosine substrate and displace the tyrosine. Cys 215 is present as a thiolate in the ground state; its pKa is reduced by interactions with Ser 222 and Arg 221. The departing tyrosine leaving group is protonated by Asp 181 acting as a general acid.|
In the second step, the cysteinyl-phosphate is hydrolysed. Asp 181 deprotonates the nucleophilic water molecule while the negative charge that accumulates on the departing thiolate leaving group is stabilised by a hydrogen bond from Ser 222.
Catalytic Sites for 1bzc
| Annotated By Reference To The Literature - Site 1 (Perform Site Search)|
|Residue||Chain||Number||UniProtKB Number||Functional Part||Function||Target||Description|
|Arg||A||221||221||macie:sideChain||Lowers the pKa of Cys 215 to allow it to exist as a thiolate. |
|Asp||A||181||181||macie:sideChain||Protonates the departing tyrosine during formation of the cysteinyl phosphate intermediate. Deprotonates the nucleophilic water molecule during hydrolysis of the intermediate.|
|Cys||A||215||215||macie:sideChain||Attacks the phosphate of the phosphotyrosine substrate, forming a cysteinyl-phosphate intermediate which is subsequently hydrolysed.|
|Ser||A||222||222||macie:sideChain||Lowers the pKa of Cys 215 to allow it to exist as a thiolate. Stabilises accumulation of negative charge on the departing cysteine thiolate during hydrolysis of the cysteinyl-phosphate.|
|Notes:||Gln 262 plays an important role in positioning the nucleophilic water molecule (see reference pubmed ID 9553104).
In addition to its effect on Cys 215, Arg 221 is important for phosphate binding. It has also been proposed to stabilise negative charge in the transition state for phosphoryl transfer. However the mechanism is thought to proceed via a largely dissociative, rather than associative, mechanism (see references pubmed ID 12188687 and pubmed ID 9553104), and in this case placing positive charges around the phosphate would not be catalytic.|
Visualization of the cysteinyl-phosphate intermediate of a protein-tyrosine phosphatase by x-ray crystallography.
J Biol Chem 1998 273 10454-10462
Functional characterization and crystal structure of the C215D mutant of protein-tyrosine phosphatase-1B.
J Biol Chem 2003 278 29009-29015
Density functional study of the mechanism of a tyrosine phosphatase: I. Intermediate formation.
J Am Chem Soc 2002 124 10225-10235
Stabilization of charges and protonation states in the active site of protein tyrosine phosphatatses: a computational study
J Phys Chem B 2000 104 11321-11333
Crystal structure of human protein tyrosine phosphatase 1B.
Science 1994 263 1397-1404