7dc8

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Crystal structure of Switch Ab Fab and hIL6R in complex with ATP

Structural highlights

7dc8 is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.757Å
Ligands:ATP, SO4
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

IL6RA_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 PubMed

The 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.

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Citations
12 reviews cite this structure
Charge reversal nano-systems for tumor therapy.
Zhang et al. (2022)
11 more
11 other articles
No citations found

See Also

References

  1. ↑ Martens AS, Bode JG, Heinrich PC, Graeve L. The cytoplasmic domain of the interleukin-6 receptor gp80 mediates its basolateral sorting in polarized madin-darby canine kidney cells. J Cell Sci. 2000 Oct;113 ( Pt 20):3593-602. PMID:11017875
  2. ↑ Buk DM, Renner O, Graeve L. Increased association with detergent-resistant membranes/lipid rafts of apically targeted mutants of the interleukin-6 receptor gp80. Eur J Cell Biol. 2005 Oct;84(10):819-31. PMID:16270750
  3. ↑ Martens AS, Bode JG, Heinrich PC, Graeve L. The cytoplasmic domain of the interleukin-6 receptor gp80 mediates its basolateral sorting in polarized madin-darby canine kidney cells. J Cell Sci. 2000 Oct;113 ( Pt 20):3593-602. PMID:11017875
  4. ↑ Buk DM, Renner O, Graeve L. Increased association with detergent-resistant membranes/lipid rafts of apically targeted mutants of the interleukin-6 receptor gp80. Eur J Cell Biol. 2005 Oct;84(10):819-31. PMID:16270750
  5. ↑ 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. Exploitation of Elevated Extracellular ATP to Specifically Direct Antibody to Tumor Microenvironment. Cell Rep. 2020 Dec 22;33(12):108542. PMID:33357423 doi:10.1016/j.celrep.2020.108542

Contents


PDB ID 7dc8

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OCA

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