4R3W

Crystal Structure Analysis of the 1,2,3-tricarboxylate benzoic acid bound to sp-ASADH-2'5'-ADP complex

4R3W の概要

• エントリーDOI: 10.2210/pdb4r3w/pdb
• 関連するPDBエントリー: 4R3N 4R41 4R4J 4R51 4R54 4R5H 4R5M
• 分子名称: Aspartate-semialdehyde dehydrogenase, SODIUM ION, benzene-1,2,3-tricarboxylic acid, ... (7 entities in total)
• 機能のキーワード: dehydrogenase, nicotineamid-dinucleotide, oxidoreductase
• 由来する生物種: Streptococcus pneumoniae
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 81704.08

構造登録者

Pavlovsky, A.G.,Viola, R.E. (登録日: 2014-08-18, 公開日: 2014-12-10, 最終更新日: 2023-09-20)

主引用文献

Pavlovsky, A.G.,Thangavelu, B.,Bhansali, P.,Viola, R.E.
A cautionary tale of structure-guided inhibitor development against an essential enzyme in the aspartate-biosynthetic pathway.
Acta Crystallogr.,Sect.D, 70:3244-3252, 2014

PubMed Abstract: The aspartate pathway is essential for the production of the amino acids required for protein synthesis and of the metabolites needed in bacterial development. This pathway also leads to the production of several classes of quorum-sensing molecules that can trigger virulence in certain microorganisms. The second enzyme in this pathway, aspartate β-semialdehyde dehydrogenase (ASADH), is absolutely required for bacterial survival and has been targeted for the design of selective inhibitors. Fragment-library screening has identified a new set of inhibitors that, while they do not resemble the substrates for this reaction, have been shown to bind at the active site of ASADH. Structure-guided development of these lead compounds has produced moderate inhibitors of the target enzyme, with some selectivity observed between the Gram-negative and Gram-positive orthologs of ASADH. However, many of these inhibitor analogs and derivatives have not yet achieved the expected enhanced affinity. Structural characterization of these enzyme-inhibitor complexes has provided detailed explanations for the barriers that interfere with optimal binding. Despite binding in the same active-site region, significant changes are observed in the orientation of these bound inhibitors that are caused by relatively modest structural alterations. Taken together, these studies present a cautionary tale for issues that can arise in the systematic approach to the modification of lead compounds that are being used to develop potent inhibitors.

PubMed: 25478842
DOI: 10.1107/S1399004714023979

実験手法

X-RAY DIFFRACTION (1.91 Å)