9Y8R
Crystal structure of the Kelch domain of human KLHL12 with compound 9h
This is a non-PDB format compatible entry.
Summary for 9Y8R
| Entry DOI | 10.2210/pdb9y8r/pdb |
| Descriptor | Kelch-like protein 12, 2-(2-amino-4-methyl-1H-1,3-benzimidazol-1-yl)-N-[2-chloro-4-(hydroxymethyl)-3-methylphenyl]acetamide (3 entities in total) |
| Functional Keywords | e3 ligase, fragment-based drug discovery, protac, ligase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 32507.76 |
| Authors | Amporndanai, K.,Madrigal-Carrillo, E.A.,Rietz, T.A.,Zhao, B.,Fesik, S.W. (deposition date: 2025-09-11, release date: 2026-04-08) |
| Primary citation | 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., 2026 Cited by 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: 41906311DOI: 10.1021/acs.jmedchem.5c02931 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.334 Å) |
Structure validation
Download full validation report
