full-length shp2 construct  (Novartis)

Journal: Chemical reviews

Article Title: Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases

doi: 10.1021/acs.chemrev.7b00105

Figure Lengend Snippet: Allosteric regulation of SHP2. (A) The schematic representation of SHP2 structure and allosteric regulation. (B) The comparison of N-SH2 domain conformation at I (gray) and A (cyan) state. (C) The pY peptide binding surface in N-SH2 domain at I and A state. BG- and EF-loop are depicted in purple and yellow, respectively. (D) The N-SH2/PTP interaction surface in the N-SH2 domain at the I and A state.

Article Snippet: 262 – 263 Utilizing the full-length SHP2 construct and screening for compounds that can block SHP2 activation by an N-SH2 domain binding pTyr peptide, the Novartis team identified several small molecule compounds that stabilize the auto-inhibited SHP2 conformation.

Techniques: Comparison, Binding Assay

Journal: Chemical reviews

Article Title: Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases

doi: 10.1021/acs.chemrev.7b00105

Figure Lengend Snippet: Disease associated SHP2 mutations. (A) NS/cancer-associated SHP2 mutations mainly reside at the interface of N-SH2 and PTP domains. (B) LS-associated SHP2 mutations only appear within the PTP domain.

Article Snippet: 262 – 263 Utilizing the full-length SHP2 construct and screening for compounds that can block SHP2 activation by an N-SH2 domain binding pTyr peptide, the Novartis team identified several small molecule compounds that stabilize the auto-inhibited SHP2 conformation.

Techniques:

Journal: Chemical reviews

Article Title: Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases

doi: 10.1021/acs.chemrev.7b00105

Figure Lengend Snippet: LS SHP2 mutations reduce SHP2 phosphatase activity by disturbing different step(s) in the catalytic process. In this figure, SHP2 wild-type (gray) and mutant (green) were superimposed onto PTP1B (cyan) structure representing transition state 1 or 2 to show mutation-induced disturbance at each specific step. Residue numbers are shown in blue for PTP1B and black for SHP2. Red dash lines represent mutation induced steric conflicts.

Article Snippet: 262 – 263 Utilizing the full-length SHP2 construct and screening for compounds that can block SHP2 activation by an N-SH2 domain binding pTyr peptide, the Novartis team identified several small molecule compounds that stabilize the auto-inhibited SHP2 conformation.

Techniques: Activity Assay, Mutagenesis, Residue

Journal: Chemical reviews

Article Title: Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases

doi: 10.1021/acs.chemrev.7b00105

Figure Lengend Snippet: The binding modes for two allosteric PTP inhibitors. (A) SHP099 binds at the inter-domain interfaces of SHP2 to stabilize the autoinhibited conformation. (B) Analog 3 binds at the trimer interfaces of PRL1 to prevent trimer formation.

Article Snippet: 262 – 263 Utilizing the full-length SHP2 construct and screening for compounds that can block SHP2 activation by an N-SH2 domain binding pTyr peptide, the Novartis team identified several small molecule compounds that stabilize the auto-inhibited SHP2 conformation.

Techniques: Binding Assay

Journal: Chemical reviews

Article Title: Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases

doi: 10.1021/acs.chemrev.7b00105

Figure Lengend Snippet: Allosteric regulation of SHP2. (A) The schematic representation of SHP2 structure and allosteric regulation. (B) The comparison of N-SH2 domain conformation at I (gray) and A (cyan) state. (C) The pY peptide binding surface in N-SH2 domain at I and A state. BG- and EF-loop are depicted in purple and yellow, respectively. (D) The N-SH2/PTP interaction surface in the N-SH2 domain at the I and A state.

Article Snippet: 262 – 263 Utilizing the full-length SHP2 construct and screening for compounds that can block SHP2 activation by an N-SH2 domain binding pTyr peptide, the Novartis team identified several small molecule compounds that stabilize the auto-inhibited SHP2 conformation.

Techniques: Binding Assay

Journal: Chemical reviews

Article Title: Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases

doi: 10.1021/acs.chemrev.7b00105

Figure Lengend Snippet: Disease associated SHP2 mutations. (A) NS/cancer-associated SHP2 mutations mainly reside at the interface of N-SH2 and PTP domains. (B) LS-associated SHP2 mutations only appear within the PTP domain.

Article Snippet: 262 – 263 Utilizing the full-length SHP2 construct and screening for compounds that can block SHP2 activation by an N-SH2 domain binding pTyr peptide, the Novartis team identified several small molecule compounds that stabilize the auto-inhibited SHP2 conformation.

Techniques:

Journal: Chemical reviews

Article Title: Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases

doi: 10.1021/acs.chemrev.7b00105

Figure Lengend Snippet: LS SHP2 mutations reduce SHP2 phosphatase activity by disturbing different step(s) in the catalytic process. In this figure, SHP2 wild-type (gray) and mutant (green) were superimposed onto PTP1B (cyan) structure representing transition state 1 or 2 to show mutation-induced disturbance at each specific step. Residue numbers are shown in blue for PTP1B and black for SHP2. Red dash lines represent mutation induced steric conflicts.

Article Snippet: 262 – 263 Utilizing the full-length SHP2 construct and screening for compounds that can block SHP2 activation by an N-SH2 domain binding pTyr peptide, the Novartis team identified several small molecule compounds that stabilize the auto-inhibited SHP2 conformation.

Techniques: Activity Assay, Mutagenesis

Journal: Chemical reviews

Article Title: Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases

doi: 10.1021/acs.chemrev.7b00105

Figure Lengend Snippet: The binding modes for two allosteric PTP inhibitors. (A) SHP099 binds at the inter-domain interfaces of SHP2 to stabilize the autoinhibited conformation. (B) Analog 3 binds at the trimer interfaces of PRL1 to prevent trimer formation.

Article Snippet: 262 – 263 Utilizing the full-length SHP2 construct and screening for compounds that can block SHP2 activation by an N-SH2 domain binding pTyr peptide, the Novartis team identified several small molecule compounds that stabilize the auto-inhibited SHP2 conformation.

Techniques: Binding Assay