Summary for 5DZL
| Entry DOI | 10.2210/pdb5dzl/pdb |
| Related | 4QXW |
| Descriptor | Carcinoembryonic antigen-related cell adhesion molecule 1 (1 entity in total) |
| Functional Keywords | cell adhesion |
| Biological source | Homo sapiens (Human) |
| Cellular location | Isoform 1: Cell membrane ; Single-pass type I membrane protein . Isoform 2: Secreted . Isoform 3: Secreted . Isoform 4: Secreted . Isoform 5: Cell membrane; Single-pass type I membrane protein. Isoform 6: Cell membrane; Single-pass type I membrane protein. Isoform 7: Cell membrane; Single-pass type I membrane protein. Isoform 8: Cell membrane ; Single-pass type I membrane protein . Cell projection, microvillus membrane ; Single-pass type I membrane protein : P13688 |
| Total number of polymer chains | 4 |
| Total formula weight | 47945.00 |
| Authors | Huang, Y.H.,Russell, A.,Gandhi, A.K.,Kondo, Y.,Chen, Q.,Petsko, G.A.,Blumberg, R.S. (deposition date: 2015-09-25, release date: 2015-10-07, Last modification date: 2023-09-27) |
| Primary citation | Huang, Y.H.,Zhu, C.,Kondo, Y.,Anderson, A.C.,Gandhi, A.,Russell, A.,Dougan, S.K.,Petersen, B.S.,Melum, E.,Pertel, T.,Clayton, K.L.,Raab, M.,Chen, Q.,Beauchemin, N.,Yazaki, P.J.,Pyzik, M.,Ostrowski, M.A.,Glickman, J.N.,Rudd, C.E.,Ploegh, H.L.,Franke, A.,Petsko, G.A.,Kuchroo, V.K.,Blumberg, R.S. CEACAM1 regulates TIM-3-mediated tolerance and exhaustion. Nature, 517:386-390, 2015 Cited by PubMed Abstract: T-cell immunoglobulin domain and mucin domain-3 (TIM-3, also known as HAVCR2) is an activation-induced inhibitory molecule involved in tolerance and shown to induce T-cell exhaustion in chronic viral infection and cancers. Under some conditions, TIM-3 expression has also been shown to be stimulatory. Considering that TIM-3, like cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1), is being targeted for cancer immunotherapy, it is important to identify the circumstances under which TIM-3 can inhibit and activate T-cell responses. Here we show that TIM-3 is co-expressed and forms a heterodimer with carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), another well-known molecule expressed on activated T cells and involved in T-cell inhibition. Biochemical, biophysical and X-ray crystallography studies show that the membrane-distal immunoglobulin-variable (IgV)-like amino-terminal domain of each is crucial to these interactions. The presence of CEACAM1 endows TIM-3 with inhibitory function. CEACAM1 facilitates the maturation and cell surface expression of TIM-3 by forming a heterodimeric interaction in cis through the highly related membrane-distal N-terminal domains of each molecule. CEACAM1 and TIM-3 also bind in trans through their N-terminal domains. Both cis and trans interactions between CEACAM1 and TIM-3 determine the tolerance-inducing function of TIM-3. In a mouse adoptive transfer colitis model, CEACAM1-deficient T cells are hyper-inflammatory with reduced cell surface expression of TIM-3 and regulatory cytokines, and this is restored by T-cell-specific CEACAM1 expression. During chronic viral infection and in a tumour environment, CEACAM1 and TIM-3 mark exhausted T cells. Co-blockade of CEACAM1 and TIM-3 leads to enhancement of anti-tumour immune responses with improved elimination of tumours in mouse colorectal cancer models. Thus, CEACAM1 serves as a heterophilic ligand for TIM-3 that is required for its ability to mediate T-cell inhibition, and this interaction has a crucial role in regulating autoimmunity and anti-tumour immunity. PubMed: 25363763DOI: 10.1038/nature13848 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.4006 Å) |
Structure validation
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