title: Structures of Two Melanoma-Associated Antigens Suggest Allosteric Regulation of Effector Binding.
abstract: The MAGE (melanoma associated antigen) protein family are tumour-associated proteins normally present only in reproductive tissues such as germ cells of the testis. The human genome encodes over 60 MAGE genes of which one class (containing MAGE-A3 and MAGE-A4) are exclusively expressed in tumours, making them an attractive target for the development of targeted and immunotherapeutic cancer treatments. Some MAGE proteins are thought to play an active role in driving cancer, modulating the activity of E3 ubiquitin ligases on targets related to apoptosis. Here we determined the crystal structures of MAGE-A3 and MAGE-A4. Both proteins crystallized with a terminal peptide bound in a deep cleft between two tandem-arranged winged helix domains. MAGE-A3 (but not MAGE-A4), is predominantly dimeric in solution. Comparison of MAGE-A3 and MAGE-A3 with a structure of an effector-bound MAGE-G1 suggests that a major conformational rearrangement is required for binding, and that this conformational plasticity may be targeted by allosteric binders.
authors.affiliation: Structural Genomics Consortium, University of Oxford, ORCRB, Roosevelt Drive, Oxford, OX3 7DQ, United Kingdom.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Newman
authors.affiliation: Structural Genomics Consortium, University of Oxford, ORCRB, Roosevelt Drive, Oxford, OX3 7DQ, United Kingdom.
authors.forename: Christopher D O
authors.initials: CD
authors.lastname: Cooper
authors.affiliation: Structural Genomics Consortium, University of Oxford, ORCRB, Roosevelt Drive, Oxford, OX3 7DQ, United Kingdom.
authors.forename: Anette K
authors.initials: AK
authors.lastname: Roos
authors.affiliation: Structural Genomics Consortium, University of Oxford, ORCRB, Roosevelt Drive, Oxford, OX3 7DQ, United Kingdom.
authors.forename: Hazel
authors.initials: H
authors.lastname: Aitkenhead
authors.affiliation: NDORMS, University of Oxford, Botnar Research Centre, Oxford, OX3 7LD, United Kingdom.
authors.forename: Udo C T
authors.initials: UC
authors.lastname: Oppermann
authors.affiliation: Tisch Cancer Institute, Mt Sinai School of Medicine, Icahn 15-20B 1425 Madison Avenue, New York, NY, 10029, United States of America.
authors.forename: Hearn J
authors.initials: HJ
authors.lastname: Cho
authors.affiliation: Department of Structural and Chemical Biology, Box 1677, Mount Sinai School of Medicine, New York, NY, 10029, United States of America.
authors.forename: Roman
authors.initials: R
authors.lastname: Osman
authors.affiliation: Structural Genomics Consortium, University of Oxford, ORCRB, Roosevelt Drive, Oxford, OX3 7DQ, United Kingdom.
authors.forename: Opher
authors.initials: O
authors.lastname: Gileadi
mesh_terms: D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary
chemical_list: D000951:Antigens, Neoplasm; C072013:MAGEA3 protein, human; C095204:MAGEA4 protein, human; D009363:Neoplasm Proteins; D010446:Peptide Fragments