1AAX

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

Summary for 1AAX

• Entry DOI: 10.2210/pdb1aax/pdb
• Descriptor: PROTEIN TYROSINE PHOSPHATASE 1B, MAGNESIUM ION, 4-PHOSPHONOOXY-PHENYL-METHYL-[4-PHOSPHONOOXY]BENZEN, ... (4 entities in total)
• Functional Keywords: complex (hydrolase-inhibitor), hydrolase, phosphorylation, non-peptide inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Endoplasmic reticulum membrane; Peripheral membrane protein; Cytoplasmic side: P18031
• Total number of polymer chains: 1
• Total formula weight: 38022.20

Authors

Puius, Y.A.,Zhao, Y.,Sullivan, M.,Lawrence, D.,Almo, S.C.,Zhang, Z.-Y. (deposition date: 1997-01-16, release date: 1998-03-04, Last modification date: 2024-05-22)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.9 Å)