8gho | pdb_00008gho

GUCY2C-peptide bound to anti-GUCY2C-scFv antibody

Structural highlights

8gho 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 1.6Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

GUC2C_HUMAN Chronic infantile diarrhea due to guanylate cyclase 2C overactivity;Intestinal obstruction in the newborn due to guanylate cyclase 2C deficiency;Congenital sodium diarrhea. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry.

Function

GUC2C_HUMAN Guanylyl cyclase that catalyzes synthesis of cyclic GMP (cGMP) from GTP (PubMed:11950846, PubMed:1718270, PubMed:22436048, PubMed:22521417, PubMed:23269669). Receptor for the E.coli heat-stable enterotoxin; E.coli enterotoxin markedly stimulates the accumulation of cGMP in mammalian cells expressing GUCY2C (PubMed:1680854, PubMed:1718270). Also activated by the endogenous peptides guanylin and uroguanylin (PubMed:8381596).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7]

Publication Abstract from PubMed

The intestinal epithelial receptor Guanylyl Cyclase C (GUCY2C) is a tumor-associated cell surface antigen expressed across gastrointestinal malignancies that can serve as an efficacious target for colorectal cancer immunotherapy. Here, we describe a yeast surface-display approach combined with an orthogonal peptide-based mapping strategy to identify the GUCY2C binding epitope of a novel anti-GUCY2CxCD3 bispecific antibody (BsAb) that recently advanced into the clinic for the treatment of cancer. The target epitope was localized to the N-terminal helix H2 of human GUCY2C, which enabled the determination of the crystal structure of the minimal GUCY2C epitope in complex with the anti-GUCY2C antibody domain. To understand if this minimal epitope covers the entire antibody binding region and to investigate the impact of epitope position on the antibody's activity, we further determined the structure of this interaction in the context of the full-length extracellular domain (ECD) of GUCY2C. We found that this epitope is positioned on the protruding membrane-distal helical region of GUCY2C and that its specific location on the surface of GUCY2C dictates the close spatial proximity of the two antigen arms in a diabody arrangement essential to the tumor killing activity of GUCY2CxCD3 BsAb.

Molecular insights into recognition of GUCY2C by T-cell engaging bispecific antibody anti-GUCY2CxCD3.,Rampuria P, Mosyak L, Root AR, Svenson K, Agostino MJ, LaVallie ER Sci Rep. 2023 Aug 17;13(1):13408. doi: 10.1038/s41598-023-40467-0. PMID:37591971^[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Scott RO, Thelin WR, Milgram SL. A novel PDZ protein regulates the activity of guanylyl cyclase C, the heat-stable enterotoxin receptor. J Biol Chem. 2002 Jun 21;277(25):22934-41. PMID:11950846 doi:10.1074/jbc.M202434200
↑ de Sauvage FJ, Camerato TR, Goeddel DV. Primary structure and functional expression of the human receptor for Escherichia coli heat-stable enterotoxin. J Biol Chem. 1991 Sep 25;266(27):17912-8 PMID:1680854
↑ Singh S, Singh G, Heim JM, Gerzer R. Isolation and expression of a guanylate cyclase-coupled heat stable enterotoxin receptor cDNA from a human colonic cell line. Biochem Biophys Res Commun. 1991 Sep 30;179(3):1455-63. PMID:1718270 doi:10.1016/0006-291x(91)91736-v
↑ Fiskerstrand T, Arshad N, Haukanes BI, Tronstad RR, Pham KD, Johansson S, Håvik B, Tønder SL, Levy SE, Brackman D, Boman H, Biswas KH, Apold J, Hovdenak N, Visweswariah SS, Knappskog PM. Familial diarrhea syndrome caused by an activating GUCY2C mutation. N Engl J Med. 2012 Apr 26;366(17):1586-95. PMID:22436048 doi:10.1056/NEJMoa1110132
↑ Romi H, Cohen I, Landau D, Alkrinawi S, Yerushalmi B, Hershkovitz R, Newman-Heiman N, Cutting GR, Ofir R, Sivan S, Birk OS. Meconium ileus caused by mutations in GUCY2C, encoding the CFTR-activating guanylate cyclase 2C. Am J Hum Genet. 2012 May 4;90(5):893-9. PMID:22521417 doi:10.1016/j.ajhg.2012.03.022
↑ Arshad N, Ballal S, Visweswariah SS. Site-specific N-linked glycosylation of receptor guanylyl cyclase C regulates ligand binding, ligand-mediated activation and interaction with vesicular integral membrane protein 36, VIP36. J Biol Chem. 2013 Feb 8;288(6):3907-17. PMID:23269669 doi:10.1074/jbc.M112.413906
↑ Mann EA, Cohen MB, Giannella RA. Comparison of receptors for Escherichia coli heat-stable enterotoxin: novel receptor present in IEC-6 cells. Am J Physiol. 1993 Jan;264(1 Pt 1):G172-8. PMID:8381596 doi:10.1152/ajpgi.1993.264.1.G172
↑ Rampuria P, Mosyak L, Root AR, Svenson K, Agostino MJ, LaVallie ER. Molecular insights into recognition of GUCY2C by T-cell engaging bispecific antibody anti-GUCY2CxCD3. Sci Rep. 2023 Aug 17;13(1):13408. PMID:37591971 doi:10.1038/s41598-023-40467-0

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Scott RO, Thelin WR, Milgram SL. A novel PDZ protein regulates the activity of guanylyl cyclase C, the heat-stable enterotoxin receptor. J Biol Chem. 2002 Jun 21;277(25):22934-41. PMID:11950846 doi:10.1074/jbc.M202434200

[2] Sauvage FJ, Camerato TR, Goeddel DV. Primary structure and functional expression of the human receptor for Escherichia coli heat-stable enterotoxin. J Biol Chem. 1991 Sep 25;266(27):17912-8 PMID:1680854

[3] Singh S, Singh G, Heim JM, Gerzer R. Isolation and expression of a guanylate cyclase-coupled heat stable enterotoxin receptor cDNA from a human colonic cell line. Biochem Biophys Res Commun. 1991 Sep 30;179(3):1455-63. PMID:1718270 doi:10.1016/0006-291x(91)91736-v

[4] Fiskerstrand T, Arshad N, Haukanes BI, Tronstad RR, Pham KD, Johansson S, Håvik B, Tønder SL, Levy SE, Brackman D, Boman H, Biswas KH, Apold J, Hovdenak N, Visweswariah SS, Knappskog PM. Familial diarrhea syndrome caused by an activating GUCY2C mutation. N Engl J Med. 2012 Apr 26;366(17):1586-95. PMID:22436048 doi:10.1056/NEJMoa1110132

[5] Romi H, Cohen I, Landau D, Alkrinawi S, Yerushalmi B, Hershkovitz R, Newman-Heiman N, Cutting GR, Ofir R, Sivan S, Birk OS. Meconium ileus caused by mutations in GUCY2C, encoding the CFTR-activating guanylate cyclase 2C. Am J Hum Genet. 2012 May 4;90(5):893-9. PMID:22521417 doi:10.1016/j.ajhg.2012.03.022

[6] Arshad N, Ballal S, Visweswariah SS. Site-specific N-linked glycosylation of receptor guanylyl cyclase C regulates ligand binding, ligand-mediated activation and interaction with vesicular integral membrane protein 36, VIP36. J Biol Chem. 2013 Feb 8;288(6):3907-17. PMID:23269669 doi:10.1074/jbc.M112.413906

[7] Mann EA, Cohen MB, Giannella RA. Comparison of receptors for Escherichia coli heat-stable enterotoxin: novel receptor present in IEC-6 cells. Am J Physiol. 1993 Jan;264(1 Pt 1):G172-8. PMID:8381596 doi:10.1152/ajpgi.1993.264.1.G172

[8] Rampuria P, Mosyak L, Root AR, Svenson K, Agostino MJ, LaVallie ER. Molecular insights into recognition of GUCY2C by T-cell engaging bispecific antibody anti-GUCY2CxCD3. Sci Rep. 2023 Aug 17;13(1):13408. PMID:37591971 doi:10.1038/s41598-023-40467-0

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

8gho | pdb_00008gho

GUCY2C-peptide bound to anti-GUCY2C-scFv antibody

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools