1AAX

CRYSTAL STRUCTURE OF PROTEIN TYROSINE PHOSPHATASE 1B COMPLEXED WITH TWO BIS(PARA-PHOSPHOPHENYL)METHANE (BPPM) MOLECULES

1AAX の概要

• エントリーDOI: 10.2210/pdb1aax/pdb
• 分子名称: PROTEIN TYROSINE PHOSPHATASE 1B, MAGNESIUM ION, 4-PHOSPHONOOXY-PHENYL-METHYL-[4-PHOSPHONOOXY]BENZEN, ... (4 entities in total)
• 機能のキーワード: complex (hydrolase-inhibitor), hydrolase, phosphorylation, non-peptide inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Endoplasmic reticulum membrane; Peripheral membrane protein; Cytoplasmic side: P18031
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 38022.20

構造登録者

Puius, Y.A.,Zhao, Y.,Sullivan, M.,Lawrence, D.,Almo, S.C.,Zhang, Z.-Y. (登録日: 1997-01-16, 公開日: 1998-03-04, 最終更新日: 2024-05-22)

主引用文献

Puius, Y.A.,Zhao, Y.,Sullivan, M.,Lawrence, D.S.,Almo, S.C.,Zhang, Z.Y.
Identification of a second aryl phosphate-binding site in protein-tyrosine phosphatase 1B: a paradigm for inhibitor design.
Proc.Natl.Acad.Sci.USA, 94:13420-13425, 1997

PubMed Abstract: The structure of the catalytically inactive mutant (C215S) of the human protein-tyrosine phosphatase 1B (PTP1B) has been solved to high resolution in two complexes. In the first, crystals were grown in the presence of bis-(para-phosphophenyl) methane (BPPM), a synthetic high-affinity low-molecular weight nonpeptidic substrate (Km = 16 microM), and the structure was refined to an R-factor of 18. 2% at 1.9 A resolution. In the second, crystals were grown in a saturating concentration of phosphotyrosine (pTyr), and the structure was refined to an R-factor of 18.1% at 1.85 A. Difference Fourier maps showed that BPPM binds PTP1B in two mutually exclusive modes, one in which it occupies the canonical pTyr-binding site (the active site), and another in which a phosphophenyl moiety interacts with a set of residues not previously observed to bind aryl phosphates. The identification of a second pTyr molecule at the same site in the PTP1B/C215S-pTyr complex confirms that these residues constitute a low-affinity noncatalytic aryl phosphate-binding site. Identification of a second aryl phosphate binding site adjacent to the active site provides a paradigm for the design of tight-binding, highly specific PTP1B inhibitors that can span both the active site and the adjacent noncatalytic site. This design can be achieved by tethering together two small ligands that are individually targeted to the active site and the proximal noncatalytic site.

PubMed: 9391040
DOI: 10.1073/pnas.94.25.13420

実験手法

X-RAY DIFFRACTION (1.9 Å)