Long Stephen B, Long Meredith B, White Rebekah R, Sullenger Bruce A
Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
RNA. 2008 Dec;14(12):2504-12. doi: 10.1261/rna.1239308. Epub 2008 Oct 29.
Aptamers, an emerging class of therapeutics, are DNA or RNA molecules that are selected to bind molecular targets that range from small organic compounds to large proteins. All of the determined structures of aptamers in complex with small molecule targets show that aptamers cage such ligands. In structures of aptamers in complex with proteins that naturally bind nucleic acid, the aptamers occupy the nucleic acid binding site and often mimic the natural interactions. Here we present a crystal structure of an RNA aptamer bound to human thrombin, a protein that does not naturally bind nucleic acid, at 1.9 A resolution. The aptamer, which adheres to thrombin at the binding site for heparin, presents an extended molecular surface that is complementary to the protein. Protein recognition involves the stacking of single-stranded adenine bases at the core of the tertiary fold with arginine side chains. These results exemplify how RNA aptamers can fold into intricate conformations that allow them to interact closely with extended surfaces on non-RNA binding proteins.
适体是一类新兴的治疗剂，是经筛选可结合从小有机化合物到大型蛋白质等各种分子靶标的DNA或RNA分子。所有已确定的与小分子靶标结合的适体结构均表明，适体将此类配体包在其中。在与天然结合核酸的蛋白质结合的适体结构中，适体占据核酸结合位点，且常常模拟天然相互作用。在此，我们展示了一种与人类凝血酶（一种天然不结合核酸的蛋白质）结合的RNA适体的晶体结构，分辨率为1.9埃。该适体在肝素结合位点附着于凝血酶，呈现出与该蛋白质互补的延伸分子表面。蛋白质识别涉及三级折叠核心处单链腺嘌呤碱基与精氨酸侧链的堆积。这些结果例证了RNA适体如何能折叠成复杂构象，使其能够与非RNA结合蛋白的延伸表面紧密相互作用。
