In silico mutagenesis: a case study of the melanocortin 4 receptor.
In silico mutagenesis: a case study of the melanocortin 4 receptor.
复制标题
DOI：
10.1096/fj.08-127530
复制
发表时间：
2009-09
期刊：
影响因子：
--
通讯作者：
Rost B
中科院分区：
文献类型：
--
作者：
Bromberg Y;Overton J;Vaisse C;Leibel RL;Rost B
黑素皮质素4受体（melanocortin 4 receptor, MC4R）是一种g蛋白偶联受体（GPCR），是调节能量稳态的关键分子。在人类MC4R编码区（hMC4R）至少有159个替换已被实验描述；其中80多种是自然产生的，其中许多与肥胖有关。然而，估计功能必需残基的评估仍然不完整。在这里，我们进行了一个完整的硅诱变分析，以评估整个hMC4R蛋白（332个残基）中所有可能的非原生点突变的功能必要性。我们使用SNAP（一种量化单氨基酸（AA）取代的功能后果的方法）来计算hMC4R AA序列中每个位置上所有可能的取代的影响。我们编制了一个可变性评分，反映了一个特定的残基可能在功能上的重要程度。我们对人类黑素皮质素受体（hMC1R）和小鼠同源受体（mMC4R）进行了相同的实验，以比较高度相关序列的计算评估。三个最显著的结果是：1)我们的预测与现有的实验注释基本一致；2)该分析确定了几个可能在功能上至关重要的aa，但尚未进行实验研究；3)受体的差异分析暗示了一些残基对MC4Rs和其他gpcr（如hMC1R）特别重要。-Bromberg， Y., Overton， J., Vaisse， C., Leibel， R. L., Rost， B.硅诱变：黑素皮质素4受体的案例研究。
The melanocortin 4 receptor (MC4R) is a G-protein-coupled receptor (GPCR) and a key molecule in the regulation of energy homeostasis. At least 159 substitutions in the coding region of human MC4R (hMC4R) have been described experimentally; over 80 of those occur naturally, and many have been implicated in obesity. However, assessment of the presumably functionally essential residues remains incomplete. Here we have performed a complete in silico mutagenesis analysis to assess the functional essentiality of all possible nonnative point mutants in the entire hMC4R protein (332 residues). We applied SNAP, which is a method for quantifying functional consequences of single amino acid (AA) substitutions, to calculate the effects of all possible substitutions at each position in the hMC4R AA sequence. We compiled a mutability score that reflects the degree to which a particular residue is likely to be functionally important. We performed the same experiment for a paralogue human melanocortin receptor (hMC1R) and a mouse orthologue (mMC4R) in order to compare computational evaluations of highly related sequences. Three results are most salient: 1) our predictions largely agree with the available experimental annotations; 2) this analysis identified several AAs that are likely to be functionally critical, but have not yet been studied experimentally; and 3) the differential analysis of the receptors implicates a number of residues as specifically important to MC4Rs vs. other GPCRs, such as hMC1R.—Bromberg, Y., Overton, J., Vaisse, C., Leibel, R. L., Rost, B. In silico mutagenesis: a case study of the melanocortin 4 receptor.
登录
查看更多内容
DOI：
10.1073/pnas.89.22.10915
发表时间：
1992-11-15
影响因子：
11.1
作者：
HENIKOFF, S;HENIKOFF, JG
通讯作者：
HENIKOFF, JG
影响因子：
14.9
作者：
Bromberg Y;Rost B
通讯作者：
Rost B
DOI：
10.1016/j.bbrc.2007.10.170
发表时间：
2008-01-18
影响因子：
3.1
作者：
Kim, Do-Hun;Shin, Seung Woo;Baik, Ja-Hyun
通讯作者：
Baik, Ja-Hyun
影响因子：
5.8
作者：
Larsen, LH;Echwald, SM;Pedersen, O
通讯作者：
Pedersen, O
DOI：
10.1006/bbrc.2001.4429
发表时间：
2001-03-09
影响因子：
3.1
作者：
Frändberg, PA;Doufexis, M;Chhajlani, V
通讯作者：
Chhajlani, V