9CYQ
Crystal structure of Q78R mutant human PTP1B (PTPN1) at room temperature (298 K)
Summary for 9CYQ
| Entry DOI | 10.2210/pdb9cyq/pdb |
| Descriptor | Tyrosine-protein phosphatase non-receptor type 1, MAGNESIUM ION (3 entities in total) |
| Functional Keywords | ptp1b, phosphatase, allostery, ptp, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 37495.13 |
| Authors | Ebrahim, A.,Perdikari, A.,Woods, V.A.,Lawler, K.,Bounds, R.,Singh, N.I.,Mehlman, T.,Riley, B.T.,Sharma, S.,Morris, J.W.,Keogh, J.M.,Henning, E.,Smith, M.,Farooqi, I.S.,Keedy, D.A. (deposition date: 2024-08-02, release date: 2024-08-21, Last modification date: 2025-04-16) |
| Primary citation | Perdikari, A.,Woods, V.A.,Ebrahim, A.,Lawler, K.,Bounds, R.,Singh, N.I.,Mehlman, T.S.,Riley, B.T.,Sharma, S.,Morris, J.W.,Keogh, J.M.,Henning, E.,Smith, M.,Farooqi, I.S.,Keedy, D.A. Structures of human PTP1B variants reveal allosteric sites to target for weight loss therapy. Biorxiv, 2025 Cited by PubMed Abstract: Protein Tyrosine Phosphatase 1B (PTP1B) is a negative regulator of leptin signaling whose disruption protects against diet-induced obesity in mice. We investigated whether structural characterization of human PTP1B variant proteins might reveal precise mechanisms to target for weight loss therapy. We selected 12 rare variants for functional characterization from exomes from 997 people with persistent thinness and 200,000 people from UK Biobank. Seven of 12 variants impaired PTP1B function by increasing leptin-stimulated STAT3 phosphorylation in cells. Using room-temperature X-ray crystallography, hydrogen-deuterium exchange mass spectrometry, and computational modeling, we determined that human variants modulate the 3-dimensional structure of PTP1B through distinct allosteric conduits that energetically link distal, highly ligandable structural regions to the active site. These studies inform the design of allosteric PTP1B inhibitors for the treatment of obesity. PubMed: 39149290DOI: 10.1101/2024.08.05.603709 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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