9LP5

The crystal structure of human PTP1B

Summary for 9LP5

• Entry DOI: 10.2210/pdb9lp5/pdb
• Descriptor: Tyrosine-protein phosphatase non-receptor type 1, GLYCEROL (3 entities in total)
• Functional Keywords: phosphatase, apo, ptp1b, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 70091.85

Authors

Zhang, J.,Lin, L.,Yuchi, Z.,Luo, D. (deposition date: 2025-01-24, release date: 2026-06-10)

Primary citation

Zhang, J.,Lin, L.,Gong, N.,Li, W.,Liu, Y.,Sundarraj, R.,Li, Y.,Dong, M.,Ma, J.,Woycechowsky, K.,Mei, K.,Ge, Y.,Yuchi, Z.,Luo, D.
Structural basis of Fumosorinone-mediated allosteric inhibition of PTP1B for cancer immunotherapy.
Commun Biol, 9:-, 2026

PubMed Abstract: Protein Tyrosine Phosphatase 1B (PTP1B) is a key immune regulator in cancer and an attractive immunotherapy target, yet progress is limited by the lack of selective inhibitors. Here, we identify Fumosorinone (FU), a natural product from Isaria fumosorosea, as a potent and selective allosteric inhibitor of PTP1B. In a murine colon tumor model, FU enhances anti-tumor immunity by reshaping the microenvironment, strengthening CD8⁺ T-cell responses, and promoting M1-like macrophage polarization. Enzymatic and biophysical analyses confirm its potency and direct engagement with PTP1B. A co-crystal structure defines a previously uncharacterized allosteric pocket that stabilizes the inactive state of the enzyme. This pocket is poorly conserved across the PTP family, consistent with minimal activity toward related phosphatases except TCPTP. Guided by this insight, virtual screening identifies additional inhibitors. These findings provide a structural basis for selective PTP1B targeting and support future immunotherapy development and rational drug discovery efforts.

PubMed: 42209755
DOI: 10.1038/s42003-026-10329-2

Experimental method

X-RAY DIFFRACTION (2.406 Å)