Structure of PDB 4x3r Chain A Binding Site BS04

Receptor Information

>4x3r Chain A (length=690) Species: 9606 (Homo sapiens)

KHNMKAFLDELKAENIKKFLYNFTQIPHLAGTEQNFQLAKQIQSQWKEFG
LDSVELAHYDVLLSYPNKTHPNYISIINEDGNEIFNTSLFEPPPPGYENV
SDIVPPFSAFSPQGMPEGDLVYVNYARTEDFFKLERDMKINCSGKIVIAR
YGKVFRGNKVKNAQLAGAKGVILYSDPADYFAPGVKSYPDGWNLPGGGVQ
RGNILNLNGAGDPLTPGYPANEYAYRRGIAEAVGLPSIPVHPIGYYDAQK
LLEKMGGSAPPDSSWRGSLKVPYNVGPGFTGNFSTQKVKMHIHSTNEVTR
IYNVIGTLRGAVEPDRYVILGGHRDSWVFGGIDPQSGAAVVHEIVRSFGT
LKKEGWRPRRTILFASWDAEEFGLLGSTEWAEENSRLLQERGVAYINADS
SIEGNYTLRVDCTPLMYSLVHNLTKELKSPDEGFEGKSLYESWTKKSPSP
EFSGMPRISKLGSGNDFEVFFQRLGIASGRARYTKNWETSGYPLYHSVYE
TYELVEKFYDPMFKYHLTVAQVRGGMVFELANSIVLPFDCRDYAVVLRKY
ADKIYSISMKHPQEMKTYSVSFDSLFSAVKNFTEIASKFSERLQDFNPIV
LRMMNDQLMFLERAFIDPLGLPDRPFYRHVIYAPSSHNKYAGESFPGIYD
ALFDIESKVDPSKAWGEVKRQIYVAAFTVQAAAETLSEVA

Ligand information

• Ligand ID: 686
• InChI: InChI=1S/C60H59BrN8O14/c61-39-8-4-36(5-9-39)35-69(22-2-1-3-48(58(78)79)63-60(82)64-49(59(80)81)19-21-53(72)73)56(75)38-7-20-52(62-34-38)67-27-23-65(24-28-67)40-10-12-41(13-11-40)66-25-29-68(30-26-66)55(74)37-6-16-44(57(76)77)47(31-37)54-45-17-14-42(70)32-50(45)83-51-33-43(71)15-18-46(51)54/h4-18,20,31-34,48-49,70H,1-3,19,21-30,35H2,(H,72,73)(H,76,77)(H,78,79)(H,80,81)(H2,63,64,82)/t48-,49-/m0/s1
• InChIKey: HNPUHOJFAXMPAU-GTMCEHENSA-N
• SMILES:
  ACDLabs 12.01: O=C(O)C(NC(=O)NC(C(=O)O)CCCCN(C(=O)c1ccc(nc1)N8CCN(c2ccc(cc2)N7CCN(C(=O)c6cc(C=3c5c(OC=4C=3C=CC(=O)C=4)cc(O)cc5)c(C(=O)O)cc6)CC7)CC8)Cc9ccc(Br)cc9)CCC(=O)O
  CACTVS 3.385: OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCN(Cc1ccc(Br)cc1)C(=O)c2ccc(nc2)N3CCN(CC3)c4ccc(cc4)N5CCN(CC5)C(=O)c6ccc(C(O)=O)c(c6)C7=C8C=CC(=O)C=C8Oc9cc(O)ccc79)C(O)=O)C(O)=O
  OpenEye OEToolkits 1.9.2: c1cc(ccc1CN(CCCCC(C(=O)O)NC(=O)NC(CCC(=O)O)C(=O)O)C(=O)c2ccc(nc2)N3CCN(CC3)c4ccc(cc4)N5CCN(CC5)C(=O)c6ccc(c(c6)C7=C8C=CC(=O)C=C8Oc9c7ccc(c9)O)C(=O)O)Br
  OpenEye OEToolkits 1.9.2: c1cc(ccc1CN(CCCC[C@@H](C(=O)O)NC(=O)N[C@@H](CCC(=O)O)C(=O)O)C(=O)c2ccc(nc2)N3CCN(CC3)c4ccc(cc4)N5CCN(CC5)C(=O)c6ccc(c(c6)C7=C8C=CC(=O)C=C8Oc9c7ccc(c9)O)C(=O)O)Br
  CACTVS 3.385: OC(=O)CC[CH](NC(=O)N[CH](CCCCN(Cc1ccc(Br)cc1)C(=O)c2ccc(nc2)N3CCN(CC3)c4ccc(cc4)N5CCN(CC5)C(=O)c6ccc(C(O)=O)c(c6)C7=C8C=CC(=O)C=C8Oc9cc(O)ccc79)C(O)=O)C(O)=O
• Formula: C60 H59 Br N8 O14
• Name: N-({(1S)-5-[(4-bromobenzyl)({6-[4-(4-{4-[4-carboxy-3-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoyl]piperazin-1-yl}phenyl)piperazin-1-yl]pyridin-3-yl}carbonyl)amino]-1-carboxypentyl}carbamoyl)-L-glutamic acid
• ChEMBL: CHEMBL3578201
• PDB chain: 4x3r Chain A Residue 1320

Receptor-Ligand Complex Structure

Structure summary

• PDB: 4x3r Design of highly potent urea-based, exosite-binding inhibitors selective for glutamate carboxypeptidase II.
• Resolution: 1.86 Å
• Binding residue (original residue number in PDB): K207 R210 E424 L428 R463 R511 G518 N519 R536 W541 Y552 H553 K699 Y700
• Binding residue (residue number reindexed from 1): K153 R156 E370 L374 R409 R457 G464 N465 R482 W487 Y495 H496 K639 Y640
• Annotation score: 1
• Binding affinity: MOAD: Ki=0.0086nM
  PDBbind-CN: -logKd/Ki=11.07,Ki=8.6pM
  BindingDB: Ki=0.008600nM

Enzymatic activity

• Enzyme Commision number: 3.4.17.21: glutamate carboxypeptidase II.

Gene Ontology

Molecular Function

• GO:0004180 carboxypeptidase activity
• GO:0004181 metallocarboxypeptidase activity
• GO:0008233 peptidase activity
• GO:0008237 metallopeptidase activity
• GO:0016805 dipeptidase activity
• GO:0046872 metal ion binding
• GO:1904492 Ac-Asp-Glu binding
• GO:1904493 tetrahydrofolyl-poly(glutamate) polymer binding

Biological Process

• GO:0006508 proteolysis
• GO:0006760 folic acid-containing compound metabolic process
• GO:0035609 C-terminal protein deglutamylation

Cellular Component

• GO:0005737 cytoplasm
• GO:0005886 plasma membrane
• GO:0009986 cell surface
• GO:0016020 membrane
• GO:0070062 extracellular exosome

External links

• PDB: RCSB:4x3r, PDBe:4x3r, PDBj:4x3r
• PDBsum: 4x3r
• PubMed: 25923815
• UniProt: Q04609|FOLH1_HUMAN Glutamate carboxypeptidase 2 (Gene Name=FOLH1)