Interactions between human glutamate carboxypeptidase II and urea-based inhibitors: structural characterization.
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.
Barinka
Cyril
C
Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA.
Byun
Youngjoo
Y
Dusich
Crystal L
CL
Banerjee
Sangeeta R
SR
Chen
Ying
Y
Castanares
Mark
M
Kozikowski
Alan P
AP
Mease
Ronnie C
RC
Pomper
Martin G
MG
Lubkowski
Jacek
J
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*
D007477:Ions; D008024:Ligands; D018698:Glutamic Acid; D014443:Tyrosine; D014508:Urea; D043425:Glutamate Carboxypeptidase II; D015032:Zinc