5XJ3

Complex structure of ipilimumab-scFv and CTLA-4

Summary for 5XJ3

• Entry DOI: 10.2210/pdb5xj3/pdb
• Related: 5XJ4
• Descriptor: ipilimumab-VH, ipilimumab-VL, Cytotoxic T-lymphocyte protein 4 (3 entities in total)
• Functional Keywords: ipilimumab, ctla-4, complex structure, immune system
• Biological source: Homo sapiens; More
• Cellular location: Cell membrane ; Single-pass type I membrane protein : P16410
• Total number of polymer chains: 12
• Total formula weight: 154673.56

Authors

He, M.,Chai, Y.,Qi, J.,Tong, Z.,Tan, S.,Gao, G.F. (deposition date: 2017-04-29, release date: 2018-04-25, Last modification date: 2024-10-23)

Primary citation

He, M.,Chai, Y.,Qi, J.,Zhang, C.W.H.,Tong, Z.,Shi, Y.,Yan, J.,Tan, S.,Gao, G.F.
Remarkably similar CTLA-4 binding properties of therapeutic ipilimumab and tremelimumab antibodies
Oncotarget, 8:67129-67139, 2017

PubMed Abstract: Monoclonal antibody based immune checkpoint blockade therapies have achieved clinical successes in management of malignant tumors. As the first monoclonal antibody targeting immune checkpoint molecules entered into clinics, the molecular basis of ipilimumab-based anti-CTLA-4 blockade has not yet been fully understood. In the present study, we report the complex structure of ipilimumab and CTLA-4. The complex structure showed similar contributions from VH and VL of ipilimumab in binding to CTLA-4 front β-sheet strands. The blockade mechanism of ipilimumab is that the strands of CTLA-4 contributing to the binding to B7-1 or B7-2 were occupied by ipilimumab and thereafter prevents the binding of B7-1 or B7-2 to CTLA-4. Though ipilimumab binds to the same epitope with tremelimumab on CTLA-4 with similar binding affinity, the higher dissociation rate of ipilimumab may indicate the dynamic binding to CTLA-4, which may affect its pharmacokinetics. The molecular basis of ipilimumab-based anti-CTLA-4 blockade and comparative study of the binding characteristics of ipilimumab and tremelimumab would shed light for the discovery of small molecular inhibitors and structure-based monoclonal antibody optimization or new biologics.

PubMed: 28978021
DOI: 10.18632/oncotarget.18004

Experimental method

X-RAY DIFFRACTION (3.2 Å)