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Nat Commun:高福院士揭示PD-1抗体作用的结构学机制

2017-02-10 佚名 生物通

中科院微生物研究所严景华研究员与高福院士近期合作接连在Nature Communications,以及Science Translational Medicine杂志上发表文章,分别报道了nivolumab阻断PD-1/PD-L1 相互作用模式和PD-1蛋白糖基化修饰对其结合 nivolumab 的影响。

中科院微生物研究所严景华研究员与高福院士近期合作接连在Nature Communications杂志上发表文章,报道了nivolumab阻断PD-1/PD-L1 相互作用模式和PD-1蛋白糖基化修饰对其结合 nivolumab 的影响。

Nivolumab是百时美-施贵宝公司开发的 PD-1 靶向性抗体药物,于2014年获得美国食品药品监督管理局(FDA)加速批准,用于黑色素瘤及非小细胞肺癌等恶性肿瘤的治疗。在第一篇文章中,研究组成员发现位于 PD-1 分子胞外免疫球蛋白功能域外的 N 端 loop 区域(N-loop)介导了其与 nivolumab 主要的氢键相互作用,而通过表面等离子共振技术(SPR)分析 nivolumab 与 PD-1 的亲和力,发现 N-loop 缺失的 PD-1 完全丧失了与 nivolumab 结合的能力,因此,N-loop 在 PD-1 与 nivolumab 相互作用中发挥了至关重要的作用。

Nivolumab 的临床前研究报告表明其与 PD-1 的结合可能依赖于 PD-1 的糖基化修饰,而肿瘤细胞内源性表达的 PD-1 可能会由于糖基转移酶功能异常而导致 PD-1 糖基化修饰异常,从而使得 nivolumab 治疗效果受到影响,因此,研究人员对 PD-1 的糖基化修饰情况及其对 nivolumab 相互作用的影响进行了研究。在 PD-1 的结构中能够观察到其第 58 位天冬酰胺糖基化修饰位点的糖链修饰,然而通过 SPR 实验对 nivolumab 与 PD-1 的 4 个 N - 糖基化位点分别突变后蛋白的亲和力检测显示其与野生型 PD-1 蛋白亲和力并无显着差异。不仅如此,nivolumab 与无糖基修饰能力的原核细胞及差异性糖基修饰的昆虫细胞表达的 PD-1 之间相互作用的亲和力与哺乳动物细胞表达产生的 PD-1 无显着差异,表明 nivolumab 与 PD-1 的相互作用并不依赖于 PD-1 的糖基化修饰。通过 nivolumab 和 pembrolizumab 与 PD-1 相互作用模式的比较发现,二者结合 PD-1 不同区域,尽管其在 PD-1 上的结合面相互紧邻,但二者并未发生交互重叠。通过 OCTEC 对二者竞争 / 协同结合特性进行分析表明,PD-1 结合 niovlumab 后不能再有效结合 pembrolizumab,反之亦然。

因此,尽管 nivolumab 和 pembrolizumab 结合 PD-1 的不同区域,其结合 PD-1 后产生的空间位阻对于进一步结合另一个抗体具有一定空间位阻效应。

原始出处;

Shuguang Tan, Hao Zhang, Yan Chai, et al.An unexpected N-terminal loop in PD-1 dominates binding by nivolumab. Nature Communications.2016 Dec 21.

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    2017-09-05 liuli5079
  2. [GetPortalCommentsPageByObjectIdResponse(id=2086942, encodeId=87c9208694259, content=<a href='/topic/show?id=490750196b' target=_blank style='color:#2F92EE;'>#COMMUN#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=71, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5019, encryptionId=490750196b, topicName=COMMUN)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7931272, createdName=liuli5079, createdTime=Tue Sep 05 10:30:00 CST 2017, time=2017-09-05, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1881648, encodeId=38211881648cb, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=72, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Sun Apr 23 14:30:00 CST 2017, time=2017-04-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=175757, encodeId=e12a1e575723, content=好文,值得点赞,值得拥有,值得收藏!, beContent=null, objectType=article, channel=null, level=null, likeNumber=112, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo7s7ZCKOmmbBTD6nE7gcd5OZpvyGEzkxBP3S275k5ZJVrsPkotZhBglRHM9rKvcj1OgkssqhcnoPw8zIaMZTF8c/0, createdBy=4c441942088, createdName=ylzr123, createdTime=Sun Feb 12 13:49:57 CST 2017, time=2017-02-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1577078, encodeId=c1c415e70787e, content=<a href='/topic/show?id=a2a613914cd' target=_blank style='color:#2F92EE;'>#PD-1抗体#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=88, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=13914, encryptionId=a2a613914cd, topicName=PD-1抗体)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=021d16387966, createdName=1249857fm37暂无昵称, createdTime=Sun Feb 12 07:30:00 CST 2017, time=2017-02-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=175516, encodeId=82841e551677, content=每天学点新进展, beContent=null, objectType=article, channel=null, level=null, likeNumber=112, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=071c2012037, createdName=wmu姿, createdTime=Sat Feb 11 09:07:18 CST 2017, time=2017-02-11, status=1, ipAttribution=)]
    2017-04-23 liye789132251
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    2017-02-12 ylzr123

    好文,值得点赞,值得拥有,值得收藏!

    0

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    2017-02-11 wmu姿

    每天学点新进展

    0

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12月29日,“2016中国科学年度新闻人物” 评选正式揭晓,高福、南仁东、潘建伟、李东、杨广文、朱枞鹏、林群、童文、杨永岗、李河君等十人榜上有名。据介绍,这项由《中国科学报》、科学网、《医学科学报》和《科学新闻》杂志共同主办的公益活动,旨在通过公众广泛参与,评出2016年度人们心目中的“科学明星”和“知识英雄”。据组委会介绍,该奖项的评奖标准是,获奖人应于2016年间在科学技术领域作出过重大创新

Cell:高福与颜宁教授揭示胆固醇转运和埃博拉病毒入侵关键机制

2016年5月26日,国际著名生物学权威杂志《Cell》在线发表微生物研究所高福院士团队和清华大学颜宁课题组的合作文章Structural  Insights into the Niemann-Pick C1 (NPC1)-Mediated Cholesterol Transfer and Ebola Infection,首次报导了人类胆固醇转运体NPC1,以及NPC1与埃博拉病毒表

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