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首页> 外文期刊>Biochemistry >The Seventh Transmembrane Domains of the delta and kappa Opioid Receptors Have Different Accessibility Patterns and Interhelical Interactions
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The Seventh Transmembrane Domains of the delta and kappa Opioid Receptors Have Different Accessibility Patterns and Interhelical Interactions

机译：Delta和Kappa阿片受体的七跨膜结构域具有不同的可接近性模式和互生相互作用

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摘要

We applied the substituted cysteine accessibility method(SCAM)to map the residues of the transmembrane helices(TMs)7 of delta and kappa opioid receptors(delta OR and kappa OR)that are on the water-accessible surface of the binding-site crevices.A total of 25 consecutive residues(except C7.38)in the TMs 7 were mutated to Cys,one at a time,and each mutant was expressed in HEK 293 cells.Most mutants displayed similar binding affinity for [~3H]diprenorphine,an antagonist,as the wild types.Pretreatment with(2-aminoethyl)methanethiosulfonate(MTSEA)inhibited [~3H]diprenorphine binding to eight delta OR and eight kappa OR mutants.All mutants except delta OR L7.52(317)C were protected by naloxone from the MTSEA effect,indicating that the side chains of V7.31(296),A7.34(299),17.39(304),L7.41-(306),G7.42(307),P7.50(315),and Y7.53(318)of delta OR and S7.34(311),F7.37(314),17.39(316),A7.40-(317),L7.41(318),G7.42(319),Y7.43(320),and N7.49(326)of kappa OR are on the water-accessible surface of the binding pockets.Combining the SCAM data with rhodopsin-based molecular models of the receptors led to the following conclusions,(i)The residues of the extracellular portion of TM7 predicted to face TM1 are sensitive to MTSEA in kappa OR but are not in delta OR.Thus,TM1 may be closer to TM7 in delta OR than in kappa OR.(ii)MTSEA-sensitive mutants start at position 7.31(296)in delta OR and at 7.34(311)in kappa OR,suggesting that TM7 in delta OR may have an additional helical turn(from 7.30 to 7.33).(iii)There is a conserved hydrogen-bond network linking D2.50 of the NLxxxD motif in TM2 with W6.48 of the CWxP motif in TM6.(iv)The NPxxY motif in TM7 interacts with TM2,TM6,and helix 8 to maintain receptors in inactive states.To the best of our knowledge,this represents the first such comparison of the structures of two highly homologous GPCRs.
机译：我们施加了取代的半胱氨酸可访问方法（ScAM）以映射达达和κApioid受体（Delta或Kappa或）的跨膜螺旋（TMS）7的残留物，所述粘合位点裂缝的可进样表面上。在TMS 7中总共25个连续的残基（C7.38除外）突变为Cys，一次突变，并且每个突变体以HEK 293细胞表达。大多数突变体为[〜3H]乙醇晶体显示出类似的结合亲和力拮抗剂，作为野生类型。用（2-氨基乙基）甲基亲烯酸盐（MTSEA）抑制[〜3H]乙炔酰胺结合到8阶段或八个κ或八次κ或突变体。除δ或L7.52（317）C中的突变体受到保护Naloxone来自妊娠的效果，表明V7.31（296），A7.34（299），17.39（304），L7.41-（306），G7.42（307），P7.50（ 315）和δ或S7.34（311），F7.37（314），17.39（316），A7.40-（317），L7.41（318），G7的Y7.53（318）。 42（319），Y7.43（320）和Kappa的N7.49（326）或在BI的可进入水面上Nding Pockets.com与受体的基于罗多蛋白酶的分子模型的诈骗数据导致了以下结论，（i）预测面部TM1的TM7的细胞外部分的残留对κBkappa或者不是在三角洲的.thus，TM1可以更接近三角洲的TM7或者比在κB中的TM7或。（ii）敏感突变体在Δα中达到7.31（296）的位置，或在Kappa中的7.34（311），或者表明三角洲的TM7可以具有额外的螺旋转（从7.30至7.33）。（iii）在TM6中的TM2中的TM2中的NLXXXD基序的D2.50的保守氢键网络连接D2.50。（IV）NPXXY TM7中的图案与TM2，TM6和HELIX 8相互作用，以保持非活动状态的受体。对于我们所知，这代表了两个高度同源GPCR结构的第一个这样的比较。

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  • 来源
    《Biochemistry》 |2005年第49期|共12页
  • 作者

    Wei Xu; Mercedes Campillo; Leonardo Pardo; J.Kim de Riel; Lee-Yuan Liu-Chen;

  • 作者单位

    Department of Pharmacology and Center for Substance Abuse Research and Fels Institute for Molecular Biology and Cancer Research Temple University School of Medicine Philadelphia PA 19140 and Laboratori de Medicina Computational Unitat de Bioestadisti;

    Department of Pharmacology and Center for Substance Abuse Research and Fels Institute for Molecular Biology and Cancer Research Temple University School of Medicine Philadelphia PA 19140 and Laboratori de Medicina Computational Unitat de Bioestadisti;

    Department of Pharmacology and Center for Substance Abuse Research and Fels Institute for Molecular Biology and Cancer Research Temple University School of Medicine Philadelphia PA 19140 and Laboratori de Medicina Computational Unitat de Bioestadisti;

    Department of Pharmacology and Center for Substance Abuse Research and Fels Institute for Molecular Biology and Cancer Research Temple University School of Medicine Philadelphia PA 19140 and Laboratori de Medicina Computational Unitat de Bioestadisti;

    Department of Pharmacology and Center for Substance Abuse Research and Fels Institute for Molecular Biology and Cancer Research Temple University School of Medicine Philadelphia PA 19140 and Laboratori de Medicina Computational Unitat de Bioestadisti;

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  • 中图分类 生物化学;
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