Structure and target interaction of a G-quadruplex RNA-aptamer

TY - JOUR

T1 - Structure and target interaction of a G-quadruplex RNA-aptamer

AU - Szameit, Kristina

AU - Berg, Katharina

AU - Kruspe, Sven

AU - Valentini, Erica

AU - Magbanua, Eileen

AU - Kwiatkowski, Marcel

AU - Chauvot de Beauchêne, Isaure

AU - Krichel, Boris

AU - Schamoni, Kira

AU - Uetrecht, Charlotte

AU - Svergun, Dmitri I

AU - Schlüter, Hartmut

AU - Zacharias, Martin

AU - Hahn, Ulrich

PY - 2016/7/29

Y1 - 2016/7/29

N2 - G-quadruplexes have recently moved into focus of research in nucleic acids, thereby evolving in scientific significance from exceptional secondary structure motifs to complex modulators of gene regulation. Aptamers (nucleic acid based ligands with recognition properties for a specific target) that form G-quadruplexes may have particular potential for therapeutic applications as they combine the characteristics of specific targeting and G-quadruplex mediated stability and regulation. We have investigated the structure and target interaction properties of one such aptamer: AIR-3 and its truncated form AIR-3A. These RNA aptamers are specific for human interleukin-6 receptor (hIL-6R), a key player in inflammatory diseases and cancer, and have recently been exploited for in vitro drug delivery studies. With the aim to resolve the RNA structure, global shape, RNA:protein interaction site and binding stoichiometry, we now investigated AIR-3 and AIR-3A by different methods including RNA structure probing, Small Angle X-ray scattering and microscale thermophoresis. Our findings suggest a broader spectrum of folding species than assumed so far and remarkable tolerance towards different modifications. Mass spectrometry based binding site analysis, supported by molecular modeling and docking studies propose a general G-quadruplex affinity for the target molecule hIL-6R.

AB - G-quadruplexes have recently moved into focus of research in nucleic acids, thereby evolving in scientific significance from exceptional secondary structure motifs to complex modulators of gene regulation. Aptamers (nucleic acid based ligands with recognition properties for a specific target) that form G-quadruplexes may have particular potential for therapeutic applications as they combine the characteristics of specific targeting and G-quadruplex mediated stability and regulation. We have investigated the structure and target interaction properties of one such aptamer: AIR-3 and its truncated form AIR-3A. These RNA aptamers are specific for human interleukin-6 receptor (hIL-6R), a key player in inflammatory diseases and cancer, and have recently been exploited for in vitro drug delivery studies. With the aim to resolve the RNA structure, global shape, RNA:protein interaction site and binding stoichiometry, we now investigated AIR-3 and AIR-3A by different methods including RNA structure probing, Small Angle X-ray scattering and microscale thermophoresis. Our findings suggest a broader spectrum of folding species than assumed so far and remarkable tolerance towards different modifications. Mass spectrometry based binding site analysis, supported by molecular modeling and docking studies propose a general G-quadruplex affinity for the target molecule hIL-6R.

U2 - 10.1080/15476286.2016.1212151

DO - 10.1080/15476286.2016.1212151

M3 - SCORING: Journal article

C2 - 27471797

VL - 13

SP - 973

EP - 987

JO - DEV BIOL

JF - DEV BIOL

SN - 0012-1606

IS - 10

ER -