5MT0

COMPLEMENT FACTOR D IN COMPLEX WITH A REVERSIBLE INDOLE CARBOXYLIC ACID BASED INHIBITOR

5MT0 の概要

• エントリーDOI: 10.2210/pdb5mt0/pdb
• 分子名称: Complement factor D, 5-fluoranyl-3-[[(1~{S},2~{S})-2-phenylcyclopropyl]carbonylamino]-1~{H}-indole-2-carboxylic acid, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: 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: 25173.52

構造登録者

Mac Sweeney, A.,Ostermann, N. (登録日: 2017-01-06, 公開日: 2017-02-15, 最終更新日: 2024-10-09)

主引用文献

Vulpetti, A.,Randl, S.,Rudisser, S.,Ostermann, N.,Erbel, P.,Mac Sweeney, A.,Zoller, T.,Salem, B.,Gerhartz, B.,Cumin, F.,Hommel, U.,Dalvit, C.,Lorthiois, E.,Maibaum, J.
Structure-Based Library Design and Fragment Screening for the Identification of Reversible Complement Factor D Protease Inhibitors.
J. Med. Chem., 60:1946-1958, 2017

PubMed Abstract: Chronic dysregulation of alternative complement pathway activation has been associated with diverse clinical disorders including age-related macular degeneration and paroxysmal nocturnal hemoglobinurea. Factor D is a trypsin-like serine protease with a narrow specificity for arginine in the P1 position, which catalyzes the first enzymatic reaction of the amplification loop of the alternative pathway. In this article, we describe two hit finding approaches leading to the discovery of new chemical matter for this pivotal protease of the complement system: in silico active site mapping for hot spot identification to guide rational structure-based design and NMR screening of focused and diverse fragment libraries. The wealth of information gathered by these complementary approaches enabled the identification of ligands binding to different subpockets of the latent Factor D conformation and was instrumental for understanding the binding requirements for the generation of the first known potent noncovalent reversible Factor D inhibitors.

PubMed: 28157311
DOI: 10.1021/acs.jmedchem.6b01684

実験手法

X-RAY DIFFRACTION (1.29 Å)