4HSG

Crystal structure of human PRMT3 in complex with an allosteric inhibitor (PRMT3- KTD)

4HSG の概要

• エントリーDOI: 10.2210/pdb4hsg/pdb
• 分子名称: PRMT3 protein, 1-(1,2,3-benzothiadiazol-6-yl)-3-(2-oxo-2-phenylethyl)urea, UNKNOWN ATOM OR ION, ... (4 entities in total)
• 機能のキーワード: prmt3, allosteric inhibitor, structural genomics, structural genomics consortium, sgc, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 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: 38594.26

構造登録者

Dobrovetsky, E.,Dong, A.,Liu, F.,Li, F.,Tempel, W.,Siarheyeva, A.,Hajian, T.,Smil, D.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.M.,Brown, P.J.,Schapira, M.,Jin, J.,Vedadi, M.,Structural Genomics Consortium (SGC) (登録日: 2012-10-30, 公開日: 2012-12-05, 最終更新日: 2023-09-20)

主引用文献

Liu, F.,Li, F.,Ma, A.,Dobrovetsky, E.,Dong, A.,Gao, C.,Korboukh, I.,Liu, J.,Smil, D.,Brown, P.J.,Frye, S.V.,Arrowsmith, C.H.,Schapira, M.,Vedadi, M.,Jin, J.
Exploiting an allosteric binding site of PRMT3 yields potent and selective inhibitors.
J. Med. Chem., 56:2110-2124, 2013

PubMed Abstract: Protein arginine methyltransferases (PRMTs) play an important role in diverse biological processes. Among the nine known human PRMTs, PRMT3 has been implicated in ribosomal biosynthesis via asymmetric dimethylation of the 40S ribosomal protein S2 and in cancer via interaction with the DAL-1 tumor suppressor protein. However, few selective inhibitors of PRMTs have been discovered. We recently disclosed the first selective PRMT3 inhibitor, which occupies a novel allosteric binding site and is noncompetitive with both the peptide substrate and cofactor. Here we report comprehensive structure-activity relationship studies of this series, which resulted in the discovery of multiple PRMT3 inhibitors with submicromolar potencies. An X-ray crystal structure of compound 14u in complex with PRMT3 confirmed that this inhibitor occupied the same allosteric binding site as our initial lead compound. These studies provide the first experimental evidence that potent and selective inhibitors can be created by exploiting the allosteric binding site of PRMT3.

PubMed: 23445220
DOI: 10.1021/jm3018332

実験手法

X-RAY DIFFRACTION (2.3 Å)