生物化学与生物物理进展
生物化學與生物物理進展
생물화학여생물물리진전
PROGRESS IN BIOCHEMISTRY AND BIOPHYSICS
2006年
9期
861-868
,共8页
肾上腺素受体%组成性活性%进化踪迹方法%G蛋白耦联受体%同源模建
腎上腺素受體%組成性活性%進化蹤跡方法%G蛋白耦聯受體%同源模建
신상선소수체%조성성활성%진화종적방법%G단백우련수체%동원모건
adrenergic receptor%constitutive activity%evolutionary trace%G protein coupled receptors(GPCR)%homology modeling
β2肾上腺素受体(β2 adrenergic receptor,β2 AR)是G蛋白耦联受体(G protein coupled receptors,GPCRs)超家族中的一员,也是研究治疗哮喘的关键药物受体靶标.采用进化踪迹(evolutionary trace,ET)方法分析肾上腺素受体家族跨膜区片段序列,识别出了44个保守的残基,然后将β2肾上腺素受体以及受体D130N活性突变体、D79N失活突变体进行分子动力学模拟,试图找出与受体不同功能状态相关的结构动力学特征.发现受体DRY motif中的D130远离R131而转向K149残基这一结构特征与受体活性高度关联,此外,从残基相互作用的变化推断出了受体helix 2,4 and 6伴随着受体活化而发生的运动.这些研究结果对进一步探索β2肾上腺素受体突变体的激活机制以及所诱发疾病的分子机理提供了依据.
β2腎上腺素受體(β2 adrenergic receptor,β2 AR)是G蛋白耦聯受體(G protein coupled receptors,GPCRs)超傢族中的一員,也是研究治療哮喘的關鍵藥物受體靶標.採用進化蹤跡(evolutionary trace,ET)方法分析腎上腺素受體傢族跨膜區片段序列,識彆齣瞭44箇保守的殘基,然後將β2腎上腺素受體以及受體D130N活性突變體、D79N失活突變體進行分子動力學模擬,試圖找齣與受體不同功能狀態相關的結構動力學特徵.髮現受體DRY motif中的D130遠離R131而轉嚮K149殘基這一結構特徵與受體活性高度關聯,此外,從殘基相互作用的變化推斷齣瞭受體helix 2,4 and 6伴隨著受體活化而髮生的運動.這些研究結果對進一步探索β2腎上腺素受體突變體的激活機製以及所誘髮疾病的分子機理提供瞭依據.
β2신상선소수체(β2 adrenergic receptor,β2 AR)시G단백우련수체(G protein coupled receptors,GPCRs)초가족중적일원,야시연구치료효천적관건약물수체파표.채용진화종적(evolutionary trace,ET)방법분석신상선소수체가족과막구편단서렬,식별출료44개보수적잔기,연후장β2신상선소수체이급수체D130N활성돌변체、D79N실활돌변체진행분자동역학모의,시도조출여수체불동공능상태상관적결구동역학특정.발현수체DRY motif중적D130원리R131이전향K149잔기저일결구특정여수체활성고도관련,차외,종잔기상호작용적변화추단출료수체helix 2,4 and 6반수착수체활화이발생적운동.저사연구결과대진일보탐색β2신상선소수체돌변체적격활궤제이급소유발질병적분자궤리제공료의거.
Beta2 adrenergic receptor (β2 AR) is one member of G protein coupled receptors (GPCRs), which is a key pharmaceutical target in the treatment of asthma. Evolutionary trace (ET) method was employed to analyze AR sequences and 44 conserved residues were identified. Then molecular dynamics (MD) simulation of the β2 wild-type receptor, D130N active mutant and D79N inactive mutant were carried out and tried to explore the structural/dynamic features characterizing functionally different states of the receptor,by means of investigating ET identified conserved basic residues in the wild-type receptor and its two mutants. Particularly, it was found that the departing of D130 from R131 of DRY motif and approaching to K149 are highly correlated with the receptor activation,and the movement of helix 2, 4 and 6 upon receptor activation is inferred from the observation that R151 and K270 interact with other residues in the receptor active state on the basis of little change of the side chain orientations. The results might provide further insights into the activating mechanism of β2 AR mutants, as well as the molecular bases of the diseases induced by the mutations of the receptor.
