3sje | pdb_00003sje

X-ray structure of human glutamate carboxypeptidase II (the E424A inactive mutant) in complex with N-acetyl-aspartyl-aminononanoic acid

spinqualitylabelsall models 3sje, resolution 1.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3sje is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.7Å Ligands: BMA, CA, CL, MAN, NAG, SDR, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function FOLH1_HUMAN Has both folate hydrolase and N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) activity. Has a preference for tri-alpha-glutamate peptides. In the intestine, required for the uptake of folate. In the brain, modulates excitatory neurotransmission through the hydrolysis of the neuropeptide, N-aceylaspartylglutamate (NAAG), thereby releasing glutamate. Isoform PSM-4 and isoform PSM-5 would appear to be physiologically irrelevant. Involved in prostate tumor progression. Also exhibits a dipeptidyl-peptidase IV type activity. In vitro, cleaves Gly-Pro-AMC. Publication Abstract from PubMed 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 non-polar 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 non-polar interactions governing GCPII affinity towards novel substrates as well as formerly unnoticed plasticity of the S1' specificity pocket. Based on 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. Novel substrate-based inhibitors of human glutamate carboxypeptidase II with enhanced lipophilicity.,Plechanovova A, Byun Y, Alquicer G, Skultetyova L, Mlcochova P, Nemcova A, Kim HJ, Navratil M, Mease RC, Lubkowski J, Pomper MG, Konvalinka J, Rulisek L, Barinka C J Med Chem. 2011 Sep 19. PMID:21923190 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Carboxypeptidase 3D structures

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