A defined structural unit enables de novo design of small-molecule–binding proteins

doi:10.1126/science.abb8330

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DOI	10.1126/science.abb8330
	A defined structural unit enables de novo design of small-molecule–binding proteins
	Nicholas F. Polizzi; William F. DeGrado
	2020-09-04
发表期刊	Science
出版年	2020
英文摘要	Protein design can compute protein folds from first principles. However, designing new proteins that are functional remains challenging, in part because designing binding interactions requires simultaneous optimization of protein sequence and protein-ligand conformation. Polizzi and DeGrado designed proteins from scratch that bind a small-molecule drug (see the Perspective by Peacock). They introduced a new structural element called a van der Mer (vdM), which tracks the orientation of a chemical group relative to the backbone of a contacting residue. Assuming proteins bind ligands using interactions similar to intraprotein packing, they determined statistically preferred vdMs from a large set of structures in the Protein Data Bank. By including weighted vdMs in their computations, they designed two of six de novo proteins that bind the drug apixaban. A drug-protein x-ray crystal structure confirmed the designed model. Science , this issue p. [1227][1]; see also p. [1166][2] The de novo design of proteins that bind highly functionalized small molecules represents a great challenge. To enable computational design of binders, we developed a unit of protein structure—a van der Mer (vdM)—that maps the backbone of each amino acid to statistically preferred positions of interacting chemical groups. Using vdMs, we designed six de novo proteins to bind the drug apixaban; two bound with low and submicromolar affinity. X-ray crystallography and mutagenesis confirmed a structure with a precisely designed cavity that forms favorable interactions in the drug–protein complex. vdMs may enable design of functional proteins for applications in sensing, medicine, and catalysis. [1]: /lookup/doi/10.1126/science.abb8330 [2]: /lookup/doi/10.1126/science.abd4791
领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/293270
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Nicholas F. Polizzi,William F. DeGrado. A defined structural unit enables de novo design of small-molecule–binding proteins[J]. Science,2020.
APA	Nicholas F. Polizzi,&William F. DeGrado.(2020).A defined structural unit enables de novo design of small-molecule–binding proteins.Science.
MLA	Nicholas F. Polizzi,et al."A defined structural unit enables de novo design of small-molecule–binding proteins".Science (2020).