3SJG

Human glutamate carboxypeptidase II (E424A inactive mutant ) in complex with N-acetyl-aspartyl-aminooctanoic acid

Summary for 3SJG

• Entry DOI: 10.2210/pdb3sjg/pdb
• Related: 3SJE 3SJF 3SJX
• Related PRD ID: PRD_000797
• Descriptor: Glutamate carboxypeptidase 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• Functional Keywords: hydrolase, metallopeptidase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane; Single-pass type II membrane protein. Isoform PSMA': Cytoplasm: Q04609
• Total number of polymer chains: 1
• Total formula weight: 83023.23

Authors

Plechanovova, A.,Byun, Y.,Alquicer, G.,Skultetyova, L.,Mlcochova, P.,Nemcova, A.,Kim, H.,Navratil, M.,Mease, R.,Lubkowski, J.,Pomper, M.,Konvalinka, J.,Rulisek, L.,Barinka, C. (deposition date: 2011-06-21, release date: 2011-10-05, Last modification date: 2020-07-29)

Primary citation

Plechanovova, A.,Byun, Y.,Alquicer, G.,Skultetyova, L.,Mlcochova, P.,Nemcova, A.,Kim, H.J.,Navratil, M.,Mease, R.,Lubkowski, J.,Pomper, M.,Konvalinka, J.,Rulisek, L.,Barinka, C.
Novel Substrate-Based Inhibitors of Human Glutamate Carboxypeptidase II with Enhanced Lipophilicity.
J.Med.Chem., 54:7535-7546, 2011

PubMed Abstract: Virtually all low molecular weight inhibitors of human glutamate carboxypeptidase II (GCPII) are highly polar compounds that have limited use in settings where more lipophilic molecules are desired. Here we report the identification and characterization of GCPII inhibitors with enhanced liphophilicity that are derived from a series of newly identified dipeptidic GCPII substrates featuring nonpolar aliphatic side chains at the C-terminus. To analyze the interactions governing the substrate recognition by GCPII, we determined crystal structures of the inactive GCPII(E424A) mutant in complex with selected dipeptides and complemented the structural data with quantum mechanics/molecular mechanics calculations. Results reveal the importance of nonpolar interactions governing GCPII affinity toward novel substrates as well as formerly unnoticed plasticity of the S1' specificity pocket. On the basis of those data, we designed, synthesized, and evaluated a series of novel GCPII inhibitors with enhanced lipophilicity, with the best candidates having low nanomolar inhibition constants and clogD > -0.3. Our findings offer new insights into the design of more lipophilic inhibitors targeting GCPII.

PubMed: 21923190
DOI: 10.1021/jm200807m

Experimental method

X-RAY DIFFRACTION (1.65 Å)