title: Interactions between human glutamate carboxypeptidase II and urea-based inhibitors: structural characterization.
abstract: Urea-based, low molecular weight ligands of glutamate carboxypeptidase II (GCPII) have demonstrated efficacy in various models of neurological disorders and can serve as imaging agents for prostate cancer. To enhance further development of such compounds, we determined X-ray structures of four complexes between human GCPII and urea-based inhibitors at high resolution. All ligands demonstrate an invariant glutarate moiety within the S1' pocket of the enzyme. The ureido linkage between P1 and P1' inhibitor sites interacts with the active-site Zn(1)(2+) ion and the side chains of Tyr552 and His553. Interactions within the S1 pocket are defined primarily by a network of hydrogen bonds between the P1 carboxylate group of the inhibitors and the side chains of Arg534, Arg536, and Asn519. Importantly, we have identified a hydrophobic pocket accessory to the S1 site that can be exploited for structure-based design of novel GCPII inhibitors with increased lipophilicity.
authors.affiliation: Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA.
authors.forename: Cyril
authors.initials: C
authors.lastname: Barinka
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Byun
authors.forename: Crystal L
authors.initials: CL
authors.lastname: Dusich
authors.forename: Sangeeta R
authors.initials: SR
authors.lastname: Banerjee
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Mark
authors.initials: M
authors.lastname: Castanares
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
authors.forename: Ronnie C
authors.initials: RC
authors.lastname: Mease
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.forename: Jacek
authors.initials: J
authors.lastname: Lubkowski
mesh_terms: D001665:Binding Sites; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D043425:Glutamate Carboxypeptidase II / Q000737:chemistry*; D018698:Glutamic Acid / Q000737:chemistry; D006801:Humans; D007477:Ions; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D014443:Tyrosine / Q000737:chemistry; D014508:Urea / Q000737:chemistry / Q000494:pharmacology*; D015032:Zinc / Q000737:chemistry*
chemical_list: D007477:Ions; D008024:Ligands; D018698:Glutamic Acid; D014443:Tyrosine; D014508:Urea; D043425:Glutamate Carboxypeptidase II; D015032:Zinc