PDBsum entry: 1aax

Hydrolase

PDB-id: 1aax

Contents

Description

Header details

Header records

References

PROCHECK

Protein chain

297 a.a. *

Ligands

BPM-BPM

Metal ions

_MG

Waters ×233

* Residue conservation analysis

Tools

Clefts Calculation

PDB id:

1aax

Name:

Hydrolase

Title:

Crystal structure of protein tyrosine phosphatase 1b complexed with two bis(para-phosphophenyl)methane (bppm) molecules

Structure:

Protein tyrosine phosphatase 1b. Chain: a. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Cell_line: bl21. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

UniProt:

P18031 (PTN1_HUMAN)

Seq:

Struc:

Seq:

435 a.a.

Struc:

297 a.a.*

Key:	PfamA domain
Secondary structure	CATH domain

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme class:

E.C.3.1.3.48   [IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Reaction:

Protein tyrosine phosphate + H₂O = protein tyrosine + phosphate (see diagram below)

Resolution:

1.90Å

R-factor:

0.182

Authors:

Y.A.Puius,Y.Zhao,M.Sullivan,D.Lawrence,S.C.Almo,Z.-Y.Zhang

Key ref:

Y.A.Puius et al. (1997). Identification of a second aryl phosphate-binding site in protein-tyrosine phosphatase 1B: a paradigm for inhibitor design.. Proc Natl Acad Sci U S A, 94, 13420-13425. [PubMed id: 9391040] [DOI: 10.1073/pnas.94.25.13420]

Date:

16-Jan-97

Release date:

04-Mar-98

Quick_links

Procheck

Clefts

Surface

Key reference

DOI no: 10.1073/pnas.94.25.13420

Proc Natl Acad Sci U S A 94:13420-13425 (1997)

PubMed id: 9391040

Identification of a second aryl phosphate-binding site in protein-tyrosine phosphatase 1B: a paradigm for inhibitor design.

Y.A.Puius, Y.Zhao, M.Sullivan, D.S.Lawrence, S.C.Almo, Z.Y.Zhang.

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.

Selected figure(s)

Figure 3.
Fig. 3. Stereo representations of the binding modes of BPPM A (a), BPPM B (b), and pTyr B (c). Contacts represented by dashed lines are distances less than 3.6 Å, except for certain interactions with aromatic rings. Interactions between the amide nitrogens of residues 216-221 and the phosphate groups of ligand A are too numerous to represent. [Diagrams were generated with the program O (16)].

Figure 4.
Fig. 4. Schematic representations of the interactions between PTP1B/C215S and BPPM A (a), BPPM B (b), and pTyr B (c). A distance cutoff^ of 3.6 Å was used, except for certain interactions with aromatic^ rings.

Figures were selected by an automated process.