5cus

From Proteopedia

Crystal Structure of sErbB3-Fab3379 Complex

PDB ID 5cus

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Structural highlights

5cus is a 12 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 3.2Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ERBB3_HUMAN Defects in ERBB3 are the cause of lethal congenital contracture syndrome type 2 (LCCS2) [MIM:607598; also called Israeli Bedouin multiple contracture syndrome type A. LCCS2 is an autosomal recessive neurogenic form of a neonatally lethal arthrogryposis that is associated with atrophy of the anterior horn of the spinal cord. The LCCS2 syndrome is characterized by multiple joint contractures, anterior horn atrophy in the spinal cord, and a unique feature of a markedly distended urinary bladder. The phenotype suggests a spinal cord neuropathic etiology.^[1]

Function

ERBB3_HUMAN Binds and is activated by neuregulins and NTAK.^[2]

Publication Abstract from PubMed

ErbB3 (HER3) is a member of the EGF receptor (EGFR) family of receptor tyrosine kinases, which, unlike the other three family members, contains a pseudo kinase in place of a tyrosine kinase domain. In cancer, ErbB3 activation is driven by a ligand-dependent mechanism through the formation of heterodimers with EGFR, ErbB2, or ErbB4 or via a ligand-independent process through heterodimerization with ErbB2 overexpressed in breast tumors or other cancers. Here we describe the crystal structure of the Fab fragment of an antagonistic monoclonal antibody KTN3379, currently in clinical development in human cancer patients, in complex with the ErbB3 extracellular domain. The structure reveals a unique allosteric mechanism for inhibition of ligand-dependent or ligand-independent ErbB3-driven cancers by binding to an epitope that locks ErbB3 in an inactive conformation. Given the similarities in the mechanism of ErbB receptor family activation, these findings could facilitate structure-based design of antibodies that inhibit EGFR and ErbB4 by an allosteric mechanism.

Inhibition of ErbB3 by a monoclonal antibody that locks the extracellular domain in an inactive configuration.,Lee S, Greenlee EB, Amick JR, Ligon GF, Lillquist JS, Natoli EJ Jr, Hadari Y, Alvarado D, Schlessinger J Proc Natl Acad Sci U S A. 2015 Oct 27;112(43):13225-30. doi:, 10.1073/pnas.1518361112. Epub 2015 Oct 12. PMID:26460020^[3]

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

References

↑ Narkis G, Ofir R, Manor E, Landau D, Elbedour K, Birk OS. Lethal congenital contractural syndrome type 2 (LCCS2) is caused by a mutation in ERBB3 (Her3), a modulator of the phosphatidylinositol-3-kinase/Akt pathway. Am J Hum Genet. 2007 Sep;81(3):589-95. Epub 2007 Jul 24. PMID:17701904 doi:S0002-9297(07)61355-X
↑ Kinugasa Y, Ishiguro H, Tokita Y, Oohira A, Ohmoto H, Higashiyama S. Neuroglycan C, a novel member of the neuregulin family. Biochem Biophys Res Commun. 2004 Sep 3;321(4):1045-9. PMID:15358134 doi:10.1016/j.bbrc.2004.07.066
↑ Lee S, Greenlee EB, Amick JR, Ligon GF, Lillquist JS, Natoli EJ Jr, Hadari Y, Alvarado D, Schlessinger J. Inhibition of ErbB3 by a monoclonal antibody that locks the extracellular domain in an inactive configuration. Proc Natl Acad Sci U S A. 2015 Oct 27;112(43):13225-30. doi:, 10.1073/pnas.1518361112. Epub 2015 Oct 12. PMID:26460020 doi:http://dx.doi.org/10.1073/pnas.1518361112