Comprehensive analysis of loops at protein-protein interfaces for macrocycle design

被引:0
作者
Gavenonis, Jason [1 ]
Sheneman, Bradley A. [1 ]
Siegert, Timothy R. [1 ]
Eshelman, Matthew R. [1 ]
Kritzer, Joshua A. [1 ]
机构
[1] Tufts Univ, Dept Chem, Medford, MA 02155 USA
基金
美国国家卫生研究院;
关键词
SMALL-MOLECULE INHIBITORS; HOT-SPOTS; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; BINDING-ENERGY; RECEPTOR; COMPLEX; IDENTIFICATION; DETERMINANTS; DATABASE;
D O I
10.1038/NCHEMBIO.1580
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Inhibiting protein-protein interactions (PPIs) with synthetic molecules remains a frontier of chemical biology. Many PPIs have been successfully targeted by mimicking alpha-helices at interfaces, but most PPIs are mediated by nonhelical, nonstrand peptide loops. We sought to comprehensively identify and analyze these loop-mediated PPIs by writing and implementing Loop Finder, a customizable program that can identify loop-mediated PPIs within all of the protein-protein complexes in the Protein Data Bank. Comprehensive analysis of the entire set of 25,005 interface loops revealed common structural motifs and unique features that distinguish loop-mediated PPIs from other PPIs. 'Hot loops', named in analogy to protein hot spots, were identified as loops with favorable properties for mimicry using synthetic molecules. The hot loops and their binding partners represent new and promising PPIs for the development of macrocycle and constrained peptide inhibitors.
引用
收藏
页码:716 / 722
页数:7
相关论文
共 43 条
[31]   Can self-inhibitory peptides be derived from the interfaces of globular protein-protein interactions? [J].
London, Nir ;
Raveh, Barak ;
Movshovitz-Attias, Dana ;
Schueler-Furman, Ora .
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, 2010, 78 (15) :3140-3149
[32]   Macrocycles Are Great Cycles: Applications, Opportunities, and Challenges of Synthetic Macrocycles in Drug Discovery [J].
Marsault, Eric ;
Peterson, Mark L. .
JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (07) :1961-2004
[33]   Hot spots-A review of the protein-protein interface determinant amino-acid residues [J].
Moreira, Irina S. ;
Fernandes, Pedro A. ;
Ramos, Maria J. .
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, 2007, 68 (04) :803-812
[34]   Exploring β-Sheet Structure and Interactions with Chemical Model Systems [J].
Nowick, James S. .
ACCOUNTS OF CHEMICAL RESEARCH, 2008, 41 (10) :1319-1330
[35]   Spatial chemical conservation of hot spot interactions in protein-protein complexes [J].
Shulman-Peleg, Alexandra ;
Shatsky, Maxim ;
Nussinov, Ruth ;
Wolfson, Haim J. .
BMC BIOLOGY, 2007, 5
[36]   Three different binding sites of Cks1 are required for p27-ubiquitin ligation [J].
Sitry, D ;
Seeliger, MA ;
Ko, TK ;
Ganoth, D ;
Breward, SE ;
Itzhaki, LS ;
Pagano, M ;
Hershko, A .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (44) :42233-42240
[37]   Crystal structure of an antagonist mutant of human growth hormone, G120R, in complex with its receptor at 2.9 angstrom resolution [J].
Sundstrom, M ;
Lundqvist, T ;
Rodin, J ;
Giebel, LB ;
Milligan, D ;
Norstedt, G .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (50) :32197-32203
[38]  
Tsai CJ, 1997, PROTEIN SCI, V6, P53
[39]   High-Throughput Screening AlphaScreen Assay for Identification of Small-Molecule Inhibitors of Ubiquitin E3 Ligase SCFSkp2-Cks1 [J].
Ungermannova, Dana ;
Lee, Junglim ;
Zhang, Gan ;
Dallmann, H. Garry ;
McHenry, Charles S. ;
Liu, Xuedong .
JOURNAL OF BIOMOLECULAR SCREENING, 2013, 18 (08) :910-920
[40]   Peptidomimetics, a synthetic tool of drug discovery [J].
Vagner, Josef ;
Qu, Hongchang ;
Hruby, Victor J. .
CURRENT OPINION IN CHEMICAL BIOLOGY, 2008, 12 (03) :292-296