9Y8S

Crystal structure of the Kelch domain of human KLHL12 with compound 9k

これはPDB形式変換不可エントリーです。

9Y8S の概要

• エントリーDOI: 10.2210/pdb9y8s/pdb
• 分子名称: Kelch-like protein 12, 4-[2-(2-amino-4-methyl-1H-1,3-benzimidazol-1-yl)acetamido]-N-benzyl-3-chloro-2-methylbenzamide (3 entities in total)
• 機能のキーワード: e3 ligase, fragment-based drug discovery, protac, ligase
• 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: 32610.88

構造登録者

Amporndanai, K.,Madrigal-Carrillo, E.A.,Rietz, T.A.,Zhao, B.,Fesik, S.W. (登録日: 2025-09-11, 公開日: 2026-04-08, 最終更新日: 2026-04-22)

主引用文献

Waterson, A.G.,Vadukoot, A.,Jana, S.,Cui, J.,Luong, K.,Rietz, T.A.,Madrigal-Carrillo, E.A.,Lehmann, B.D.,Sensintaffar, J.L.,Zhao, B.,Amporndanai, K.,Petros, Z.A.,Scaggs, W.R.,Chacon Simon, S.,Vekariya, R.H.,Kim, K.,Thangaraj, M.,Christov, P.P.,South, T.M.,Sai, J.,Thiruvaipati, A.,Schmidt, C.R.,Eells, R.,Moore, W.J.,Olejniczak, E.T.,Phan, J.,Fesik, S.W.
Identification of KLHL12 Ligands Using Fragment-Based Methods.
J.Med.Chem., 69:7709-7731, 2026

PubMed Abstract: Targeted protein degradation can be induced by recruiting a protein of interest to an E3 ligase, resulting in its ubiquitination and subsequent proteasome-mediated degradation. However, only a small number of E3 ligases have been utilized for degradation. Expansion of the repertoire of useful E3 ligases via the identification of ligands to those ligases could broaden the scope and applicability of the degradation paradigm. We have identified KLHL12 as an E3 ligase with higher expression in cancer over normal tissues. We report here the use of NMR-based screening to identify fragments that bind to KLHL12, and X-ray structures of a fragment hit bound to KLHL12. Using this structural information, we optimized the hits, leading to the first reported small molecules that bind to KLHL12 with submicromolar affinity. Derivatives of these compounds may be useful for the construction of PROTACs to selectively degrade protein targets in tumors while sparing normal cells.

PubMed: 41906311
DOI: 10.1021/acs.jmedchem.5c02931

実験手法

X-RAY DIFFRACTION (1.286 Å)