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两种黑色素瘤相关抗原的结构表明效应子结合存在变构调节。

Structures of Two Melanoma-Associated Antigens Suggest Allosteric Regulation of Effector Binding.

作者信息

Newman Joseph A, Cooper Christopher D O, Roos Anette K, Aitkenhead Hazel, Oppermann Udo C T, Cho Hearn J, Osman Roman, Gileadi Opher

机构信息

Structural Genomics Consortium, University of Oxford, ORCRB, Roosevelt Drive, Oxford, OX3 7DQ, United Kingdom.

NDORMS, University of Oxford, Botnar Research Centre, Oxford, OX3 7LD, United Kingdom.

出版信息

PLoS One. 2016 Feb 24;11(2):e0148762. doi: 10.1371/journal.pone.0148762. eCollection 2016.

DOI:10.1371/journal.pone.0148762
PMID:26910052
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4766014/
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.

摘要

黑色素瘤相关抗原（MAGE）蛋白家族是肿瘤相关蛋白，通常仅存在于生殖组织中，如睾丸的生殖细胞。人类基因组编码60多种MAGE基因，其中一类（包含MAGE-A3和MAGE-A4）仅在肿瘤中表达，这使其成为开发靶向和免疫治疗癌症疗法的有吸引力的靶点。一些MAGE蛋白被认为在驱动癌症、调节E3泛素连接酶对与细胞凋亡相关靶点的活性方面发挥积极作用。在这里，我们确定了MAGE-A3和MAGE-A4的晶体结构。两种蛋白结晶时，末端肽结合在两个串联排列的带翼螺旋结构域之间的深裂隙中。MAGE-A3（而非MAGE-A4）在溶液中主要以二聚体形式存在。将MAGE-A3和MAGE-A3与效应物结合的MAGE-G1的结构进行比较表明，结合需要主要的构象重排，并且这种构象可塑性可能是变构结合剂的作用靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2aa5/4766014/f7fb402b149c/pone.0148762.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2aa5/4766014/60d9d2ef8b29/pone.0148762.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2aa5/4766014/036627b43f84/pone.0148762.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2aa5/4766014/90c2ffde0766/pone.0148762.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2aa5/4766014/9670f0dcf6a7/pone.0148762.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2aa5/4766014/a9f16d7a9094/pone.0148762.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2aa5/4766014/448dcd2c6100/pone.0148762.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2aa5/4766014/aa7d8018cb5c/pone.0148762.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2aa5/4766014/e27585ed392e/pone.0148762.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2aa5/4766014/f7fb402b149c/pone.0148762.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2aa5/4766014/60d9d2ef8b29/pone.0148762.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2aa5/4766014/036627b43f84/pone.0148762.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2aa5/4766014/90c2ffde0766/pone.0148762.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2aa5/4766014/9670f0dcf6a7/pone.0148762.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2aa5/4766014/a9f16d7a9094/pone.0148762.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2aa5/4766014/448dcd2c6100/pone.0148762.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2aa5/4766014/aa7d8018cb5c/pone.0148762.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2aa5/4766014/e27585ed392e/pone.0148762.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2aa5/4766014/f7fb402b149c/pone.0148762.g009.jpg

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