9y8u
Crystal structure of the Kelch domain of human KLHL12 with compound 10j
Structural highlights
FunctionKLH12_HUMAN Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a negative regulator of Wnt signaling pathway and ER-Golgi transport (PubMed:22358839, PubMed:27565346). The BCR(KLHL12) complex is involved in ER-Golgi transport by regulating the size of COPII coats, thereby playing a key role in collagen export, which is required for embryonic stem (ES) cells division: BCR(KLHL12) acts by mediating monoubiquitination of SEC31 (SEC31A or SEC31B) (PubMed:22358839, PubMed:27565346). The BCR(KLHL12) complex is also involved in neural crest specification: in response to cytosolic calcium increase, interacts with the heterodimer formed with PEF1 and PDCD6/ALG-2, leading to bridge together the BCR(KLHL12) complex and SEC31 (SEC31A or SEC31B), promoting monoubiquitination of SEC31 and subsequent collagen export (PubMed:27716508). As part of the BCR(KLHL12) complex, also acts as a negative regulator of the Wnt signaling pathway by mediating ubiquitination and subsequent proteolysis of DVL3 (PubMed:16547521). The BCR(KLHL12) complex also mediates polyubiquitination of DRD4 and PEF1, without leading to degradation of these proteins (PubMed:18303015, PubMed:20100572, PubMed:27716508).[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedTargeted 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. Identification of KLHL12 Ligands Using Fragment-Based Methods.,Waterson AG, Vadukoot A, Jana S, Cui J, Luong K, Rietz TA, Madrigal-Carrillo EA, Lehmann BD, Sensintaffar JL, Zhao B, Amporndanai K, Petros ZA, Scaggs WR, Chacon Simon S, Vekariya RH, Kim K, Thangaraj M, Christov PP, South TM, Sai J, Thiruvaipati A, Schmidt CR, Eells R, Moore WJ, Olejniczak ET, Phan J, Fesik SW J Med Chem. 2026 Mar 29. doi: 10.1021/acs.jmedchem.5c02931. PMID:41906311[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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