7dc8
From Proteopedia
Crystal structure of Switch Ab Fab and hIL6R in complex with ATP
Structural highlights
FunctionIL6RA_HUMAN Part of the receptor for interleukin 6. Binds to IL6 with low affinity, but does not transduce a signal. Signal activation necessitate an association with IL6ST. Activation may lead to the regulation of the immune response, acute-phase reactions and hematopoiesis.[1] [2] Low concentration of a soluble form of IL6 receptor acts as an agonist of IL6 activity.[3] [4] Publication Abstract from PubMedThe extracellular adenosine triphosphate (ATP) concentration is highly elevated in the tumor microenvironment (TME) and remains tightly regulated in normal tissues. Using phage display technology, we establish a method to identify an antibody that can bind to an antigen only in the presence of ATP. Crystallography analysis reveals that ATP bound in between the antibody-antigen interface serves as a switch for antigen binding. In a transgenic mouse model overexpressing the antigen systemically, the ATP switch antibody binds to the antigen in tumors with minimal binding in normal tissues and plasma and inhibits tumor growth. Thus, we demonstrate that elevated extracellular ATP concentration can be exploited to specifically target the TME, giving therapeutic antibodies the ability to overcome on-target off-tumor toxicity. Exploitation of Elevated Extracellular ATP to Specifically Direct Antibody to Tumor Microenvironment.,Mimoto F, Tatsumi K, Shimizu S, Kadono S, Haraya K, Nagayasu M, Suzuki Y, Fujii E, Kamimura M, Hayasaka A, Kawauchi H, Ohara K, Matsushita M, Baba T, Susumu H, Sakashita T, Muraoka T, Aso K, Katada H, Tanaka E, Nakagawa K, Hasegawa M, Ayabe M, Yamamoto T, Tanba S, Ishiguro T, Kamikawa T, Nambu T, Kibayashi T, Azuma Y, Tomii Y, Kato A, Ozeki K, Murao N, Endo M, Kikuta J, Kamata-Sakurai M, Ishii M, Hattori K, Igawa T Cell Rep. 2020 Dec 22;33(12):108542. doi: 10.1016/j.celrep.2020.108542. PMID:33357423[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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