5JNV

Crystal structure of bovine low molecular weight protein tyrosine phosphatase (LMPTP) mutant (W49Y N50E) complexed with HEPES

5JNV の概要

• エントリーDOI: 10.2210/pdb5jnv/pdb
• 関連するPDBエントリー: 5JNR 5JNS 5JNT 5JNU 5JNW
• 分子名称: Low molecular weight phosphotyrosine protein phosphatase, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, DIMETHYL SULFOXIDE, ... (4 entities in total)
• 機能のキーワード: protein tyrosine phosphatase, hydrolase, lmw-ptp, lmptp
• 由来する生物種: Bos taurus (Bovine)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18555.14

構造登録者

Stanford, S.M.,Aleshin, A.E.,Liddington, R.C.,Bankston, L.,Cadwell, G.,Bottini, N. (登録日: 2016-04-30, 公開日: 2017-03-29, 最終更新日: 2023-09-27)

主引用文献

Stanford, S.M.,Aleshin, A.E.,Zhang, V.,Ardecky, R.J.,Hedrick, M.P.,Zou, J.,Ganji, S.R.,Bliss, M.R.,Yamamoto, F.,Bobkov, A.A.,Kiselar, J.,Liu, Y.,Cadwell, G.W.,Khare, S.,Yu, J.,Barquilla, A.,Chung, T.D.Y.,Mustelin, T.,Schenk, S.,Bankston, L.A.,Liddington, R.C.,Pinkerton, A.B.,Bottini, N.
Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase.
Nat. Chem. Biol., 13:624-632, 2017

PubMed Abstract: Obesity-associated insulin resistance plays a central role in type 2 diabetes. As such, tyrosine phosphatases that dephosphorylate the insulin receptor (IR) are potential therapeutic targets. The low-molecular-weight protein tyrosine phosphatase (LMPTP) is a proposed IR phosphatase, yet its role in insulin signaling in vivo has not been defined. Here we show that global and liver-specific LMPTP deletion protects mice from high-fat diet-induced diabetes without affecting body weight. To examine the role of the catalytic activity of LMPTP, we developed a small-molecule inhibitor with a novel uncompetitive mechanism, a unique binding site at the opening of the catalytic pocket, and an exquisite selectivity over other phosphatases. This inhibitor is orally bioavailable, and it increases liver IR phosphorylation in vivo and reverses high-fat diet-induced diabetes. Our findings suggest that LMPTP is a key promoter of insulin resistance and that LMPTP inhibitors would be beneficial for treating type 2 diabetes.

PubMed: 28346406
DOI: 10.1038/nchembio.2344

実験手法

X-RAY DIFFRACTION (1.6 Å)