Binding efficiency of protein-protein complexes.
Binding efficiency of protein-protein complexes.
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DOI：
10.1021/bi301039t
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发表时间：
2012-11-13
期刊：
影响因子：
2.9
通讯作者：
Whitty A
中科院分区：
文献类型：
--
作者：
Day ES;Cote SM;Whitty A
我们研究可逆的蛋白质-蛋白质相互作用（PPI）的结合亲和力和界面大小之间的关系，使用细胞因子从肿瘤坏死因子（TNF）超家族及其受体作为测试用例。使用表面等离子体共振，我们测量了大受体TNFR 1与其配体TNFα（KD = 1.4 ± 0.4 nM）和光敏素-α（KD = 50 ± 10 nM）结合以及小受体Fn 14与TWEAK（KD = 70 ± 10 nM）结合的单位点结合亲和力。我们还收集了所有其他TNF/TNFR家族复合物的数据，这些复合物已报道了可靠的单位点结合亲和力。我们使用这些值来计算结合效率-定义为埋在接触界面处的表面积的每平方厘米的结合能-对于这些复合物中的九个，共晶体结构是可用的，并将结果与一组144个蛋白质-蛋白质复合物的结果进行比较，这些蛋白质-蛋白质复合物具有已公布的亲和力值。结果表明，最有效的PPI复合物产生约20 cal.mol−1/m2的结合能。稳定的复合物需要约500 μ 2的最小接触面积，需要产生足够的相互作用能以支付从1 M溶液共定位两种蛋白质的熵成本。最紧凑和有效的TNF/TNFR复合物是BAFF/BR 3，其达到最大可实现结合效率的约80%。其他小的受体也提供了高的结合效率，而较大的受体仅产生该限制的44-49%，尽管主要通过单个小结构域相互作用。结果提供了新的见解多少结合能可以产生的PPI接口的给定大小，并建立一个定量的方法来预测多大的天然或工程接触界面必须达到给定水平的结合亲和力。
We examine the relationship between binding affinity and interface size for reversible protein-protein interactions (PPI), using cytokines from the tumor necrosis factor (TNF) superfamily and their receptors as a test case. Using surface plasmon resonance, we measured single-site binding affinities for the large receptor TNFR1 binding to its ligands TNFα (KD = 1.4 ± 0.4 nM) and lymphotoxin-α (KD = 50 ± 10 nM), and also for the small receptor Fn14 binding to TWEAK (KD = 70 ± 10 nM). We additionally assembled data for all other TNF/TNFR family complexes for which reliable single site binding affinities have been reported. We used these values to calculate the binding efficiency – defined as binding energy per Å2 of surface area buried at the contact interface – for the nine of these complexes for which co-crystal structures are available, and compared the results to those for a set of 144 protein-protein complexes with published affinity values. The results show that the most efficient PPI complexes generate ~20 cal.mol−1/Å2 of binding energy. A minimum contact area of ~500 Å2 is required for a stable complex, required to generate sufficient interaction energy to pay the entropic cost of co-localizing two proteins from 1 M solution. The most compact and efficient TNF/TNFR complex was BAFF/BR3, which achieved ~80% of the maximum achievable binding efficiency. Other small receptors also gave high binding efficiencies, while the larger receptors generated only 44-49% of this limit despite interacting primarily through just a single small domain. The results provide new insight into how much binding energy can be generated by a PPI interface of a given size, and establish a quantitative method to predict how large a natural or engineered contact interface must be to achieve a given level of binding affinity.
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DOI：
10.1161/01.atv.0000062883.93715.37
发表时间：
2003-04-01
影响因子：
8.7
作者：
Donohue, PJ;Richards, CM;Winkles, JA
通讯作者：
Winkles, JA
DOI：
10.1073/pnas.0800452105
发表时间：
2008-05-27
影响因子：
11.1
作者：
Chang, Chia-en A.;McLaughlin, William A.;McCammon, J. Andrew
通讯作者：
McCammon, J. Andrew
影响因子：
2.9
作者：
Ansari, S;Helms, V
通讯作者：
Helms, V
影响因子：
2.9
作者：
Brooijmans, N;Sharp, KA;Kuntz, ID
通讯作者：
Kuntz, ID
影响因子：
2.9
作者：
Gordon, NC;Pan, B;Starovasnik, MA
通讯作者：
Starovasnik, MA