3SJF

X-ray structure of human glutamate carboxypeptidase II in complex with a urea-based inhibitor (A25)

3SJF の概要

• エントリーDOI: 10.2210/pdb3sjf/pdb
• 関連するPDBエントリー: 3SJE 3SJG 3SJX
• 分子名称: 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)
• 機能のキーワード: hydrolase, metallopeptidase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cell membrane; Single-pass type II membrane protein. Isoform PSMA': Cytoplasm: Q04609
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 83302.28

構造登録者

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. (登録日: 2011-06-21, 公開日: 2011-10-05, 最終更新日: 2024-11-27)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.65 Å)