6SGP

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

6SGP の概要

• エントリーDOI: 10.2210/pdb6sgp/pdb
• 分子名称: Glutamate carboxypeptidase 2, DI(HYDROXYETHYL)ETHER, (2~{S})-2-[[(2~{S})-1,5-bis(oxidanyl)-1,5-bis(oxidanylidene)pentan-2-yl]sulfamoylamino]pentanedioic acid, ... (13 entities in total)
• 機能のキーワード: glutamate carboxypeptidase ii (gcpii); naaladase; prostate-specific membrane antigen;sulfamide, 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: 84143.20

構造登録者

Barinka, C.,Shukla, S.,Motlova, L. (登録日: 2019-08-05, 公開日: 2020-08-26, 最終更新日: 2024-01-31)

主引用文献

Novakova, Z.,Tehrani, Z.A.,Jurok, R.,Motlova, L.,Kutil, Z.,Pavlicek, J.,Shukla, S.,Choy, C.J.,Havlinova, B.,Baranova, P.,Berkman, C.E.,Kuchar, M.,Cerny, J.,Barinka, C.
Structural, Biochemical, and Computational Characterization of Sulfamides as Bimetallic Peptidase Inhibitors.
J.Chem.Inf.Model., 2024

PubMed Abstract: The sulfonamide function is used extensively as a general building block in various inhibitory scaffolds and, more specifically, as a zinc-binding group (ZBG) of metalloenzyme inhibitors. Here, we provide biochemical, structural, and computational characterization of a metallopeptidase in complex with inhibitors, where the mono- and bisubstituted sulfamide functions are designed to directly engage zinc ions of a bimetallic enzyme site. Structural data showed that while monosubstituted sulfamides coordinate active-site zinc ions via the free negatively charged amino group in a canonical manner, their bisubstituted counterparts adopt an atypical binding pattern divergent from expected positioning of corresponding tetrahedral reaction intermediates. Accompanying quantum mechanics calculations revealed that electroneutrality of the sulfamide function is a major factor contributing to the markedly lower potency of bisubstituted compounds by considerably lowering their interaction energy with the enzyme. Overall, while bisubstituted uncharged sulfamide functions can bolster favorable pharmacological properties of a given inhibitor, their use as ZBGs in metalloenzyme inhibitors might be less advantageous due to their suboptimal metal-ligand properties.

PubMed: 38224368
DOI: 10.1021/acs.jcim.3c01542

実験手法

X-RAY DIFFRACTION (1.58 Å)