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Catalytic Site Atlas Search Results
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Catalytic Site Atlas

CSA LITERATURE entry for 2bkr

E.C. nameSENTRIN-SPECIFIC PROTEASE 8
SpeciesHomo sapiens (Human)
E.C. Number (IntEnz) 3.4.22.-
CSA Homologues of 2bkrThere are 15 Homologs
CSA Entries With UniProtID
CSA Entries With EC Number 3.4.22.-
PDBe Entry 2bkr
PDBSum Entry 2bkr
MACiE Entry 2bkr

Literature Report

IntroductionNEDP1 is a 211 residue cysteine-type peptidase of the Ulp family expressed in homo sapiens. It is a deneddylase enzyme involved in the processing of preNEDD8 to its mature form and the deconjugation of NEDD8 from modified substrates (eg. cullin). NEDP1 discrimates between NEDD8 and homologous ubiquitin, involving highly precise molecular recognition due to a single residue change in the C-terminus of NEDD8.
Mechansim1. Deprotonation of the Cys 163 sulfhydryl by an adjacent histidine residue with a basic side chain. The thiolate ion is stabilised through the formation of an ion pair with the neighbouring imidazolium group of His 102. Asp 119 is adjacent to the catalytic His 102, and its side chain amide oxygen is hydrogen bonded to the N(e2)H of His 102. This effect of this is to both stabilise the ion pair and also keep the imidazole ring of the His residue in favourable orientation. The oxyanion is stabilised by an oxyanion hole.

Catalytic Sites for 2bkr

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
TrpA103103macie:sideChainTrp 103 forms van der Vaals with Gly 75 of NEDD8. This stabilises the transition state.
HisA102102macie:sideChainThe basic side chain of the His residue deprotonates the cysteine thiol to activate it towards nucleophilic attack of the substrate peptide bond. The imidazole ring of His 102 forms an ion pair with Cys 163. His 102 forms a hydrogen bond to the Asn 91 side chain amide oxygen to stabilise the ion pair and keep the imidazole ring in favourable orientation.
AspA119119macie:sideChainAsp 119 is adjacent to the catalytic His 102, and its side chain amide oxygen is hydrogen bonded to the N(e2)H of His 340. This effect of this is to both stabilise the ion pair and also keep the imidazole ring of the His residue in favourable orientation
TrpA2626macie:sideChainTrp 26 forms van der Vaals with the C terminal Gly-Gly of NEDD8. It sits directly above the catalytic site with its side chain locking thr Gly-Gly into the active site.
CysA163163macie:sideChainDeprotonation of the cysteine thiol by the His 102 basic side chain activates the cysteine S to carry out nucleophilic attack on the carbonyl carbon of the peptide bond in the substrate. The thiolate ion is stabilised by the formation of an active site ion pair with the His 102 imidazole ring. The main chain NH of Cys 163 forms part of the oxyanion hole, which stabilises the transition state.

Literature References

Notes:
Shen LN
Structural basis of NEDD8 ubiquitin discrimination by the deNEDDylating enzyme NEDP1.
EMBO J 2005 24 1341-1351
PubMed: 15775960
Mendoza HM
NEDP1, a highly conserved cysteine protease that deNEDDylates Cullins.
J Biol Chem 2003 278 25637-25643
PubMed: 12730221
Kuo GM
Factors associated with herbal use among urban multiethnic primary care patients: a cross-sectional survey.
BMC Complement Altern Med 2004 4 18-0
PubMed: 15575960
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