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Catalytic Site Atlas

CSA LITERATURE entry for 1s95

E.C. namephosphoprotein phosphatase
SpeciesHomo sapiens (Human)
E.C. Number (IntEnz) 3.1.3.16
CSA Homologues of 1s95
CSA Entries With UniProtID P53041
CSA Entries With EC Number 3.1.3.16
PDBe Entry 1s95
PDBSum Entry 1s95
MACiE Entry 1s95

Literature Report

IntroductionSerine/threonine protein phosphatase 5 (PP5) from Homo sapiens hydrolyses a phosphoprotein substrate into a protein and a phosphate group. PP5 affects many signaling networks that regulate cell growth and cellular responses to stress. It is a member of the PPP gene family of protein phosphatases that is widely expressed in mammalian tissues.
Mechansim1. A water molecule is polarised by Mn 501, Mn 502 and His 427, lowering its pKa to such an extent that at optimal pH of the enzyme, it exists as a hydroxide. 2. This hydroxide nucleophilically attacks the phosphorus atom of the substrate, causing the P-O4 bond to break. 3. The transition state is stabilised by Arg 275 (H bonding to O1 and O4), Arg 400 (H bonding to O3) and Asn 303 (H bonding to O2). 4. Asp 274 hydrogen bonds to His 304, lowering its pKa, making His 304 more likely to donate a proton. 5. The leaving group R-O is protonated by His 304.
Reaction

Catalytic Sites for 1s95

Annotated By Reference To The Literature - Site 3 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
HisA304304macie:sideChainActs as an acid by donating a proton to the leaving group R-O.
AspA274274macie:sideChainHydrogen bonds to His 304, lowering its pKa, aiding His 304 to donate a proton to the leaving group.
ArgA400400macie:sideChainHydrogen bonds to atom O3 of the substrate, helping to stabilise the transition state.
ArgA275275macie:sideChainHydrogen bonds to atoms O1 and O4, helping to stabilise the transition state.
AsnA303303macie:sideChainHydrogen bonds to atom O2 of the substrate, helping to stabilise the transition state.
HisA427427macie:sideChainHelps lower the pKa of a bound water molecule to such an extent as to cause it to 'spontaneously deprotonate'.

Annotated By Reference To The Literature - Site 4 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
HisB304304macie:sideChainActs as an acid by donating a proton to the leaving group R-O.
AspB274274macie:sideChainHydrogen bonds to His 304, lowering its pKa, aiding His 304 to donate a proton to the leaving group.
ArgB400400macie:sideChainHydrogen bonds to atom O3 of the substrate, helping to stabilise the transition state.
ArgB275275macie:sideChainHydrogen bonds to atoms O1 and O4, helping to stabilise the transition state.
AsnB303303macie:sideChainHydrogen bonds to atom O2 of the substrate, helping to stabilise the transition state.
HisB427427macie:sideChainHelps lower the pKa of a bound water molecule to such an extent as to cause it to 'spontaneously deprotonate'.

Literature References

Notes:
Swingle MR
Structural basis for the catalytic activity of human serine/threonine protein phosphatase-5.
J Biol Chem 2004 279 33992-33999
PubMed: 15155720
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