1Z8L,2C6C,2C6G


Conserved Protein Domain Family
PA_GCPII_like

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cd02121: PA_GCPII_like 
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PA_GCPII_like: Protease-associated domain containing protein, glutamate carboxypeptidase II (GCPII)-like. This group contains various PA domain-containing proteins similar to GCPII including, GCPIII (NAALADase2) and NAALADase L. These proteins belong to the peptidase M28 family. GCPII is also known N-acetylated-alpha-linked acidic dipeptidase (NAALDase1), folate hydrolase or prostate-specific membrane antigen (PSMA). GCPII is found in various human tissues including prostate, small intestine, and the central nervous system. In the brain, GCPII is known as NAALDase1, it functions as a NAALDase hydrolyzing the neuropeptide N-acetyl-L-aspartyl-L-glutamate (alpha-NAAG), to release free glutamate. In the small intestine, GCPII releases the terminal glutamate from poly-gamma-glutamated folates. GCPII (PSMA) is a useful cancer marker; its expression is markedly increased in prostate cancer and in tumor-associated neovasculature. GCPIII hydrolyzes alpha-NAAG with a lower efficiency than does GCPII; NAALADase L is not able to hydrolyze alpha-NAAG. The GCPII PA domain (referred to as the apical domain) participates in substrate binding and may act as a protein-protein interaction domain.
Statistics
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PSSM-Id: 239036
View PSSM: cd02121
Aligned: 35 rows
Threshold Bit Score: 194.046
Threshold Setting Gi: 20138392
Created: 14-Jan-2005
Updated: 17-Jan-2013
Structure
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Program:
Drawing:
Aligned Rows:
 
Conserved site includes 2 residues -Click on image for an interactive view with Cn3D
Feature 1:substrate binding [chemical binding site]
Evidence:
  • Structure:2C6C_A, human GCPII, bound with an inhibitor Gpi-18431 (S)-2-(4- Iodobenzylphosphonomethyl)-Pentanedioic Acid, contacts with inhibitor at 3.5A
    View structure with Cn3D
  • Structure:2C6G_A, human GCPII, bound with glutamate (the product of the reaction), contacts with glutamate at 3.5 A
    View structure with Cn3D
  • Comment:The 2C6C_A and 2C6G_A structures show the PA (apical) domain interacting, with the glutarate portion of the GPI-18431 inhibitor, and with the glutamate product, respectively. The interacting PA residues form part of the GPCII S1' substrate-binding pocket. The inhibitor GPI-18431 occupies the S1 and S1' pockets; Glutamate occupies only the S1' pocket.

Sequence Alignment
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Format: Row Display: Color Bits: Type Selection:
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                                        
1Z8L_A        65 PNKTHp----nYISIInedg-neiFNTslfeppppg--yenvsdivpPFSAFSPQGMPEGDLVYVNYArtEDFFKLerdm 137
2C6C_A        77 PNKTHp----nYISIInedg-neiFNTslfeppppg--yenvsdivpPFSAFSPQGMPEGDLVYVNYArtEDFFKLerdm 149
gi 111063512 273 PDGRKva---iVDPPEkrweakleEPAvfnpp----------kaqtpAYHGMSASGNVTGPLIYVNYCdkKDFKRLwd-s 338
gi 85108335  297 PKADGraveiiDDKADngkg-kaiWSAkleendras---gltghqtwAFHGHSKTGDVRGRLIYANYGsrEDFQRIkd-l 371
gi 115396266 268 PTPGGrrv-aiVDPPDlaweaaleEKDeq----------------tpVFHGHSKSGNVTGHLVYANYGsrEDFQHLad-k 329
gi 129557004 151 PVDHRla---lLKKDGdkt--dvtFEAsleedvlkedhtsglpdrvpTFHGYSASGNVTAPFVYVNFGtyDDYQDLvd-a 224
gi 46442262  126 PSLKEd----vIDEDStt----hgNDTv------------------pTFLGYAANGNVTAEYVFVNYGtkDDFDFLke-q 178
gi 30725320   94 PVHRSl----vLTPTDsak--pitFLLeqeklgdn----pyanevmpTFHGYAKSGNVSGPVVYANYGrvEDFVRLkkdm 163
gi 115439875 120 PVHRSl----sLSAPGhat---tpFALvqdtypgdpy-aavsaeavpTFLAYAASGSVAAEAVYANYGrpEDFAYLaa-r 190
gi 20138392  126 PTHISvta-sfSNTTTl------eFDLndvpgd---------spvvrPYHAYSPSGSAQGNVVFVNHGeeRDYHALes-i 188
                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                           #                                                  #         
1Z8L_A       138 KINCSGKIVIARYGkv--fRGNKVKNAQLAGAKGVILYSDpadyfapgvks----ypdgwnlpggGVQRGNiln-lnGAG 210
2C6C_A       150 KINCSGKIVIARYGkv--fRGNKVKNAQLAGAKGVILYSDpadyfapgvks----ypdgwnlpggGVQRGNiln-lnGAG 222
gi 111063512 339 GIDVQGAIALCRTYgpqpdLAMKVKAAQNAGCVGVLVYSDpaddgfkkgnp----wpdgkwrpgeSVQRGSvaqtniIMG 414
gi 85108335  372 GIQTAGAIALVRYYgphadRALKVKAAELAGFAGCLIYSDpfddgfkkgdt----apkgpfmpadGVQRGSvslmswVVG 447
gi 115396266 330 GVSLNGSIALLRNLlvlsvVSSTPTLPRMDSFAALPIRRDvfm-------------------padGVQRGAvslmswVVG 390
gi 129557004 225 NVSLAGKIAIAKYGri--fRGLKVKRAQELGMVGVILYDDpqedgditedngykpypegparnpsAVQRGSaqflsiAPG 302
gi 46442262  179 KVNVTGKIAIARYGki--fRGLKVKFAQEHGAVGVLIYSDpgddqgitpangykqyphgparqesSVQRGSvqflsqIPG 256
gi 30725320  164 GVNVSGAVVIARYGqi--yRGDIVKNAYEAGAVGVVIYTDkrdyggdewf------paskwmppsGVQVGTvy---nGLG 232
gi 115439875 191 GVDVTGKVVLARYGkv--yRGDIVINARKAGAAAAVIYTDakdyaageaf------pdgpwmpptGVQVGStf---kGVG 259
gi 20138392  189 GVSVKGCVVLARKGen-lgRGAIVKIAEAKGALGVLIYAEndgg------------------gfgGIERGTvm---rGIG 246
                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                                        
1Z8L_A       211 DPLTPGYPANEYayrrgi---aeavglPSIPVHPIGYYDAQKLLEKmggsa----ppdssWRGSLkvpynvgpgftgnfs 283
2C6C_A       223 DPLTPGYPANEYayrrgi---aeavglPSIPVHPIGYYDAQKLLEKmggsa----ppdssWRGSLkvpynvgpgftgnfs 295
gi 111063512 415 DVTTPGKASVKKvervsq---qdnpalPKIPSLPLSWKDAQKLLQSlkdsge---klpseWRGGVpdvgdewf-sghpdt 487
gi 85108335  448 DVLTPGWGSRENmprmkk---eqtkglVKIPSLPLSWRDAKVLLQHlkgkgq---rvpedWVGGVpdvdewwt--gdhen 519
gi 115396266 391 DVLTPGFASTPEekkrlkp--eesqglNSIPSLPIAWRDAQRLLQVlqghgs---kvpakWVGGVphvdqw-----wtgd 460
gi 129557004 303 DPTTPGYPSKPGcerqd-----phnsiPSIPSLPISYQEVLPFLRAlnghgpk-asefnkRWQGGklgskgve-ynigps 375
gi 46442262  257 DPTTPGYPSKGDverkd-----phesiGRIPALPISYREVKPILAKlngfgiqpdsfageLEGFDyftg----------p 321
gi 30725320  233 DPTTPGWASVDGcerlsdeavelsgdvPLIPSLPVSAADAEVILKTvvg---------dvSDGDVypv-----------g 292
gi 115439875 260 DPTTPMWASSEGcervsipeamatddmPGIPALPVSGRDGEAILQLiggdv-----apkdWQGGDgspvy-------rlg 327
gi 20138392  247 DPVSPGWPGVVGgeklslddelvtrrfPKIPSLPLSLRNAEIILASlggar-----apleWRNSGrvgpg--------qr 313

                 ....*...
Feature 1                
1Z8L_A       284 tqKVKMHI 291
2C6C_A       296 tqKVKMHI 303
gi 111063512 488 apKVNLQN 495
gi 85108335  520 spIVRLKN 527
gi 115396266 461 enSPVVNL 468
gi 129557004 376 pdDVVINL 383
gi 46442262  322 npKYTLNL 329
gi 30725320  293 pgPGVLNL 300
gi 115439875 328 pgPAVLNL 335
gi 20138392  314 vgPGRMVI 321

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