6EZ9

X-ray structure of human glutamate carboxypeptidase II (GCPII) - the E424M inactive mutant, in complex with a inhibitor JHU3372

6EZ9 の概要

• エントリーDOI: 10.2210/pdb6ez9/pdb
• 分子名称: Glutamate carboxypeptidase 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• 機能のキーワード: glutamate carboxypeptidase ii (gcpii); naaladase; prostate-specific membrane antigen; phosphoramidate, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 83138.25

構造登録者

Barinka, C.,Novakova, Z.,Motlova, L. (登録日: 2017-11-14, 公開日: 2018-12-12, 最終更新日: 2024-11-06)

主引用文献

Barinka, C.,Novakova, Z.,Hin, N.,Bim, D.,Ferraris, D.V.,Duvall, B.,Kabarriti, G.,Tsukamoto, R.,Budesinsky, M.,Motlova, L.,Rojas, C.,Slusher, B.S.,Rokob, T.A.,Rulisek, L.,Tsukamoto, T.
Structural and computational basis for potent inhibition of glutamate carboxypeptidase II by carbamate-based inhibitors.
Bioorg.Med.Chem., 27:255-264, 2019

PubMed Abstract: A series of carbamate-based inhibitors of glutamate carboxypeptidase II (GCPII) were designed and synthesized using ZJ-43, N-[[[(1S)-1-carboxy-3-methylbutyl]amino]carbonyl]-l-glutamic acid, as a molecular template in order to better understand the impact of replacing one of the two nitrogen atoms in the urea-based GCPII inhibitor with an oxygen atom. Compound 7 containing a C-terminal 2-oxypentanedioic acid was more potent than compound 5 containing a C-terminal glutamic acid (2-aminopentanedioic acid) despite GCPII's preference for peptides containing an N-terminal glutamate as substrates. Subsequent crystallographic analysis revealed that ZJ-43 and its two carbamate analogs 5 and 7 with the same (S,S)-stereochemical configuration adopt a nearly identical binding mode while (R,S)-carbamate analog 8 containing a d-leucine forms a less extensive hydrogen bonding network. QM and QM/MM calculations have identified no specific interactions in the GCPII active site that would distinguish ZJ-43 from compounds 5 and 7 and attributed the higher potency of ZJ-43 and compound 7 to the free energy changes associated with the transfer of the ligand from bulk solvent to the protein active site as a result of the lower ligand strain energy and solvation/desolvation energy. Our findings underscore a broader range of factors that need to be taken into account in predicting ligand-protein binding affinity. These insights should be of particular importance in future efforts to design and develop GCPII inhibitors for optimal inhibitory potency.

PubMed: 30552009
DOI: 10.1016/j.bmc.2018.11.022

実験手法

X-RAY DIFFRACTION (1.61 Å)