Nature:郑宁教授揭示钙通路阻滞剂脱靶机制

2016-08-28 何嫱 生物通

一项原子水平上的分析揭示出,广泛应用于心脏病患者的两类钙通道阻滞剂,通过对钙通道分子上的不同位点起作用产生了不同的治疗效应。数百万的美国人,以及全球范围内更大数量的患者,都服用钙通道阻滞剂来控制心血管问题。在发表于8月24日《自然》(Nature)杂志上的一项研究中,研究人员描述了两种不同化学类别的钙通道阻滞剂基本作用模式的差异。这一认识是通过分析它们结合位点的原子结构而获得的。华盛顿大学药理学教



一项原子水平上的分析揭示出,广泛应用于心脏病患者的两类钙通道阻滞剂,通过对钙通道分子上的不同位点起作用产生了不同的治疗效应。

数百万的美国人,以及全球范围内更大数量的患者,都服用钙通道阻滞剂来控制心血管问题。

在发表于8月24日《自然》(Nature)杂志上的一项研究中,研究人员描述了两种不同化学类别的钙通道阻滞剂基本作用模式的差异。这一认识是通过分析它们结合位点的原子结构而获得的。

华盛顿大学药理学教授、霍华德休斯医学研究所研究员郑宁(Ning Zheng),与华盛顿大学药理学系主任及教授、医学研究员William A. Catterall共同领导了这项研究。论文的第一作者是药理学博士后研究员Lin Tang。

郑宁教授长期从事泛素化机理及其关键蛋白质结构研究,取得了一系列重要成果。在Cell、Nature和Science等国际权威杂志上发表了大量研究论文。其中Nature文章12篇,Cell文章4篇,Science论文2篇, 三篇文章成为杂志的封面故事进行推荐。

在过去的50年里一些钙通道阻滞剂被首次鉴别出来,并获得批准用作药物,已成为了心血管疾病的主要疗法。最新的研究结果可以告知我们如何设计出新版本的钙通道阻滞剂,更好、更安全地处理心跳不规则、胸痛和高血压

研究人员比较了异搏定(verapamil)一类治疗心律失常的钙通道阻滞剂,和氨氯地平(amlodipine)一类治疗高血压或心绞痛的钙通道阻滞剂。

研究小组希望了解钙通道阻滞剂分子与钙通道的互作机制。钙通道控制了跨细胞膜的钙离子流动,当心肌细胞或动脉及静脉平滑肌细胞中的这些分子孔道开放时,钙涌入细胞会触发心脏收缩泵出血液,动脉收缩使得它们的直径变窄,由此提高了血压。

通过干扰这些分子孔道,钙通道阻滞剂可以抑制太过强烈的心血管反应——这可以导致心跳不规则或高血压。

一些药理学家认为异搏定类的药物在物理上阻断了钙通道,阻止了钙离子进入到细胞中,由此恢复了正常心律,而氨氯地平类药物间接阻止了钙通道激活和孔道开放,由此防止了高血压和心绞痛。

然而,对于这些不同作用机制背后的特异结构却仍不清楚。

X射线晶体学及离子通道功能分析的发展,现在使得研究人员能够探究这些药物作用的亚分子深度。研究人员查看了药物分子结合钙通道的位点,以及这种结合改变钙通道运作的机制。

研究发现,高血压和心绞痛药物氨氯地平的结合位点是在钙通道分子的外缘。中央孔道周围有一些对电位敏感的电位感受器。

结合位点位于钙通道分子四个亚基其中两个亚基之间的中心孔结构的外缘。这种结合通过扭曲通道的形状,将一个钙离子永久嵌入其内部关闭了这一通道。

郑宁说:“氨氯地平精细地重塑了这一孔道,使得钙离子被拉到一边,自始至终只是钉在那儿,就好像它被锁定了一样。”

与之相反,异搏定分子插入钙通道的中央腔,通过自身直接阻挡了钙通道传导通路。

异搏定还利用了心脏悸动时钙通道频繁的开放,在心房颤动或心房扑动时它就是这样发挥作用的。这一孔道开放越是频繁,异搏定分子进入中央腔,封闭这一孔道的机会就越大。

Catterall说:“异搏定似乎在心脏快速跳动的部位更好地结合了钙通道,让它们减慢速度。”

他指出,华盛顿大学生理学和生物物理学教授Bertil Hille及同事们早先已在研究利多卡因(lidocaine)一类用于牙科和手术中止痛的一些局部麻醉药时,证实了快放电频率对钠离子通道阻滞剂的影响。

另一方面,在它们的静息状态下,血管细胞中的钙通道通常是关闭的。氨氯地平分子调节了电位依赖性的钙通道激活,不需要依赖通道的频繁开放来进入这一孔道。

这就是氨氯地平类松弛血管的药物,可以治疗某些原因引起高血压和心绞痛紧压疼痛,而不会对心脏自身产生重大影响的原因。这将它们与异搏定类药物区分开来,后者有利于细胞中的钙通道在心脏电路中活化。

了解这两个结合位点的细节可能会促使开发出一些更精确地进入位点的钙通道阻滞剂。更精确的形状有可能还能防止下一代版本的钙通道阻滞剂不小心对准错误的结合位点,引起不必要的副作用。

Catterall解释说:“钙通道阻滞剂是相对安全的药物。药物过量可产生毒性,导致室性心律失常,或过度抑制心肌或平滑肌细胞收缩。”

基于结构改进的药物设计可以允许更小而仍然有效的药物剂量,这样更具特异性且更安全。微调药物设计或许可以阻止其他可能促成的不必要副作用:钙通道阻滞剂脱靶阻断钠通道。


原始出处

Lin Tang,Tamer M. Gamal El-Din, Teresa M. Swanson,David C. Pryde,Todd Scheuer,Ning Zheng& William A. Catterall.Structural basis for inhibition of a voltage-gated Ca2+ channel by Ca2+ antagonist drugs.Nature 2016

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    2017-01-26 zhyy88
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    2016-09-21 仁心济世
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    2016-09-25 1e10c84am36(暂无匿称)

    文章很好值得关注

    0

  4. 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    2016-09-15 1e0ece0dm09(暂无匿称)

    谢谢指点,学习了

    0

  5. 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    2016-09-08 镱鉎鉌釚

    牛?

    0

  6. 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level=null, likeNumber=38, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=06731943211, createdName=靠近你, createdTime=Mon Aug 29 11:37:00 CST 2016, time=2016-08-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=106800, encodeId=2f1010680040, content=学习啦,谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=23, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfdY7yem1P7bRvOP6z0jKsBoYR8ezfAricY7meQWcte7LRJsWHVn0CnPJg2JuQmevR0DoFmmEib5QLD2kNESBESQT/0, createdBy=59191706502, createdName=医路开来, createdTime=Mon Aug 29 11:26:00 CST 2016, time=2016-08-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=106707, encodeId=7e98106e07fa, content=学习啦,谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfdY7yem1P7bRvOP6z0jKsBoYR8ezfAricY7meQWcte7LRJsWHVn0CnPJg2JuQmevR0DoFmmEib5QLD2kNESBESQT/0, createdBy=59191706502, createdName=医路开来, createdTime=Mon Aug 29 09:58:00 CST 2016, time=2016-08-29, status=1, ipAttribution=)]
    2016-08-31 1e0ece0dm09(暂无匿称)

    拜读了,谢谢分享

    0

  7. 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level=null, likeNumber=38, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=06731943211, createdName=靠近你, createdTime=Mon Aug 29 11:37:00 CST 2016, time=2016-08-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=106800, encodeId=2f1010680040, content=学习啦,谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=23, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfdY7yem1P7bRvOP6z0jKsBoYR8ezfAricY7meQWcte7LRJsWHVn0CnPJg2JuQmevR0DoFmmEib5QLD2kNESBESQT/0, createdBy=59191706502, createdName=医路开来, createdTime=Mon Aug 29 11:26:00 CST 2016, time=2016-08-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=106707, encodeId=7e98106e07fa, content=学习啦,谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfdY7yem1P7bRvOP6z0jKsBoYR8ezfAricY7meQWcte7LRJsWHVn0CnPJg2JuQmevR0DoFmmEib5QLD2kNESBESQT/0, createdBy=59191706502, createdName=医路开来, createdTime=Mon Aug 29 09:58:00 CST 2016, time=2016-08-29, status=1, ipAttribution=)]
    2016-08-29 wei834766788

    学习!!!

    0

  8. 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topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfdY7yem1P7bRvOP6z0jKsBoYR8ezfAricY7meQWcte7LRJsWHVn0CnPJg2JuQmevR0DoFmmEib5QLD2kNESBESQT/0, createdBy=59191706502, createdName=医路开来, createdTime=Mon Aug 29 09:58:00 CST 2016, time=2016-08-29, status=1, ipAttribution=)]
    2016-08-29 靠近你

    好方法,值得学习,谢谢分享

    0

  9. 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level=null, likeNumber=38, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=06731943211, createdName=靠近你, createdTime=Mon Aug 29 11:37:00 CST 2016, time=2016-08-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=106800, encodeId=2f1010680040, content=学习啦,谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=23, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfdY7yem1P7bRvOP6z0jKsBoYR8ezfAricY7meQWcte7LRJsWHVn0CnPJg2JuQmevR0DoFmmEib5QLD2kNESBESQT/0, createdBy=59191706502, createdName=医路开来, createdTime=Mon Aug 29 11:26:00 CST 2016, time=2016-08-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=106707, encodeId=7e98106e07fa, content=学习啦,谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfdY7yem1P7bRvOP6z0jKsBoYR8ezfAricY7meQWcte7LRJsWHVn0CnPJg2JuQmevR0DoFmmEib5QLD2kNESBESQT/0, createdBy=59191706502, createdName=医路开来, createdTime=Mon Aug 29 09:58:00 CST 2016, time=2016-08-29, status=1, ipAttribution=)]
    2016-08-29 医路开来

    学习啦,谢谢分享

    0

  10. 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createdAvatar=https://wx.qlogo.cn/mmopen/aLGWoFXAyMbIu3qymFOyheQLjPSX3OUs5GmkyBlcCOwTPIeq3why9NGibxxUqYo6hcx8qZLHZFgNPnBK1yzWeOFpyg2OnWOt0/0, createdBy=fa4716, createdName=仁心济世, createdTime=Wed Sep 21 05:00:00 CST 2016, time=2016-09-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=134818, encodeId=80c1134818d6, content=文章很好值得关注, beContent=null, objectType=article, channel=null, level=null, likeNumber=70, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzdAIB7UwTkHt6fQkBP8ictliaXtc5gCUmYdAW1sAETC2nhO3q6YjRHkUibyOCtP8ibmXNObTyd63A076/0, createdBy=d4111948983, createdName=1e10c84am36(暂无匿称), createdTime=Sun Sep 25 08:55:00 CST 2016, time=2016-09-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=127028, encodeId=8d2712e028d1, content=谢谢指点,学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=72, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/oLAjfB7s1ib06iaV3D9Tg5K46ZAxBHmHsph32KkfsWGwmickB6RsCUD8KruE4vo5CpvXfdu16GBpp4ibh6WJu1o9iatP1LWKDmvmic/0, createdBy=be6f1940165, createdName=1e0ece0dm09(暂无匿称), createdTime=Thu Sep 15 00:27:00 CST 2016, time=2016-09-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=113524, encodeId=1fe5113524fb, content=牛?, beContent=null, objectType=article, channel=null, level=null, likeNumber=72, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20160903/IMG57CA05C7ADAC62159.jpg, createdBy=ea6c1943408, createdName=镱鉎鉌釚, createdTime=Thu Sep 08 07:47:00 CST 2016, time=2016-09-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=107805, encodeId=688410e80520, content=拜读了,谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=63, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/oLAjfB7s1ib06iaV3D9Tg5K46ZAxBHmHsph32KkfsWGwmickB6RsCUD8KruE4vo5CpvXfdu16GBpp4ibh6WJu1o9iatP1LWKDmvmic/0, createdBy=be6f1940165, createdName=1e0ece0dm09(暂无匿称), createdTime=Wed Aug 31 02:05:00 CST 2016, time=2016-08-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=107012, encodeId=687c10e0121e, content=学习!!!, beContent=null, objectType=article, channel=null, level=null, likeNumber=81, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=078f1661649, createdName=wei834766788, createdTime=Mon Aug 29 22:42:00 CST 2016, time=2016-08-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=106835, encodeId=df9c10683577, content=好方法,值得学习,谢谢分享, beContent=null, objectType=article, channel=null, 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topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfdY7yem1P7bRvOP6z0jKsBoYR8ezfAricY7meQWcte7LRJsWHVn0CnPJg2JuQmevR0DoFmmEib5QLD2kNESBESQT/0, createdBy=59191706502, createdName=医路开来, createdTime=Mon Aug 29 09:58:00 CST 2016, time=2016-08-29, status=1, ipAttribution=)]
    2016-08-29 医路开来

    学习啦,谢谢分享

    0