Dissecting ligand recognition and folding of a structurally complex aptamer-gtp-complex by solution NMR Copyright edited version
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1 Dissecting ligand recognition and folding of a structurally complex aptamer-gtp-complex by solution NMR Copyright edited version Antje Wolter AK Wöhnert, Institute for Molecular Biosciences and BMRZ, Goethe-University Frankfurt am Main
2 Nucleic acid aptamers short nt, 5-30 kda defined, compact 3D structure high affinity and specificity artificially created binding of molecular targets small metal ions organic molecules peptides & proteins viruses bacteria cells targets within live animals Systematic evolution of ligands by exponential enrichment Ellington and Szostak, Nature 1990, 346; Tuerk and Gold, Science 1990, 249; Robertson and Joyce, Nature 1990, 344 for ribozymes
3 Applications for aptamers optical biosensing calorimetric aptasensors electrochemical fluorophores bioimaging probes paramagnetic compounds Pb 2+ cocaine TNT Hg 2+ hazard detection analytical & affinity reagents food antibiotics inspection bacterial infestation drug delivery antagonist therapeutics agonist alternative to diagnostics antibodies e.g. ELISA with aptamers Review see: Song et al, Sensors, 12, 2012
4 Applications for aptamers optical biosensing calorimetric aptasensors electrochemical fluorophores bioimaging probes paramagnetic compounds Pb 2+ cocaine TNT Hg 2+ hazard detection analytical & affinity reagents food antibiotics inspection bacterial infestation drug delivery antagonist therapeutics agonist alternative to diagnostics antibodies e.g. ELISA with aptamers Review see: Song et al, Sensors, 12, 2012
5 aptamers vs. antibodies aptamers antibodies small 6-20 kda size big kda diverse, flexible structure α-helix and β-fold in vitro SELEX hours - 8 weeks generation and discovery in vivo biological system > 6 months chemical solid state synthesis manufacturing animal based production? low cost high none or low batch to batch variation high none or low immunogenicity high vulnerable unmodified some minutes faster unconjugated 30 minutes but nuclease degradation half life renal filtration circulation time resistant slower up to 1 month Review see: Zhou and Rossi, Nature Reviews Drug Discovery, 16, 2017
6 Pegaptanib sodium, sold as Macugen first and so far only FDA approved aptamer therapeutic (2004) neovascular age-related macular degeneration (AMD) antagonist to vascular endothelial growth factor VEGF-165 intravitreal injection treat choroidal neovascularization eye low abundance of nucleases Review see: Ng et al., Nature Reviews Drug Discovery, 5, 2006
7 Pegaptanib sodium, sold as Macugen first and so far only FDA approved aptamer therapeutic (2004) neovascular age-related macular degeneration (AMD) antagonist to vascular endothelial growth factor VEGF-165 intravitreal injection treat choroidal neovascularization eye low abundance of nucleases highly modified RNA 2 -OMe-purines, 2 -F-pyrimidines 3-3 inverted deoxythymidine PEGylated for longer circulation time 4` 3` 5` R R= F, OCH 3 Base 1` 2` VEGF-165 Review see: Ng et al., Nature Reviews Drug Discovery, 5, 2006
8 Pegaptanib sodium, sold as Macugen first and so far only FDA approved aptamer therapeutic (2004) neovascular age-related macular degeneration (AMD) VEGF-165 antagonist to vascular endothelial growth factor VEGF-165 intravitreal injection treat choroidal neovascularization eye low abundance of nucleases highly modified RNA 2 -OMe-purines, 2 -F-pyrimidines 3-3 inverted deoxythymidine PEGylated for longer circulation time replaced by monoclonal antibodies bevacizumab (Avastin) ranibizumab (Lucentis)! 4` 3` 5` R R= F, OCH 3 Base 1` 2` Review see: Ng et al., Nature Reviews Drug Discovery, 5, 2006
9 Different approach to aptamers short ( nt) defined, compact 3D structure high affinity and specificity artificially created suitable target for investigations by solution NMR structurally very diverse bulges pseudoknots non-canonical base pairs triplets, quartets quadruplexes kissing hairpins power of NMR hydrogen bonding near native structures kinetics dynamics aptamers are great model systems for the investigation of RNA folding, RNA structure and RNA-ligand-interactions
10 Different approach to aptamers short ( nt) defined, compact 3D structure high affinity and specificity artificially created suitable target for investigations by solution NMR structurally very diverse bulges pseudoknots non-canonical base pairs triplets, quartets quadruplexes kissing hairpins power of NMR hydrogen bonding near native structures kinetics dynamics aptamers are great model systems for the investigation of RNA folding, RNA structure and RNA-ligand-interactions
11 GTP a ligand for many different aptamers Class I Class III K d = 76 nm K d = 30 nm K d = 300 nm K d = 300 nm K d = 8000 nm Class II Class IV K d =250 nm K d = 300 nm K d =400 nm K d = 900 nm 9-4 K d = 9 nm Class V K d = 17 nm GTP Davis and Szostak, PNAS 2002; Carothers et al., JACS 2004; Carothers et al., JACS 2006
12 ? Do the different secondary structures of these aptamers reflect structurally different recognition modes?? How is the aptamer structure related to affinity and selectivity?? Does ligand recognition occur through lock and key, induced fit or conformational capture mechanism?
13 Naturally occurring examples for purine recognition Mechanism of riboswitches guanine riboswitch class II cdigmp riboswitch class I cdigmp riboswitch Review: Batey, Quarterly Reviews of Biophysics 2012? How about GTP recognition
14 classic SELEX derived GTP binding RNA aptamers Class I Class III K d = 76 nm K d = 30 nm K d = 300 nm K d = 300 nm K d = 8000 nm Class II Class IV K d =250 nm K d = 300 nm K d =400 nm K d = 900 nm 9-4 K d = 9 nm Class V K d = 17 nm GTP Davis and Szostak, PNAS 2002; Carothers et al., JACS 2004; Carothers et al., JACS 2006;
15 GTP class I aptamer Class I G31 K d = 76 nm GTP G16 P2 GTP 5` 3` P1 GTP Carothers et al. RNA 2006 unaltered or reduced affinity of modified analogs
16 classic SELEX derived GTP binding RNA aptamers Class I G31 GTP G Class III K d = 76 nm K d = 30 nm K d = 300 nm K d = 300 nm K d = 8000 nm Class II Class IV K d =250 nm K d = 300 nm K d =400 nm K d = 900 nm 9-4 K d = 9 nm Class V K d = 17 nm GTP Davis and Szostak, PNAS 2002; Carothers et al., JACS 2004; Carothers et al., JACS 2006; Carothers et al, RNA 2006; Nasiri et al, RNA 2016
17 GTP class V aptamer Filtered NOESY-HSQCs GTP H8 GTP NH 2 GTP H1 GTP Nasiri et al, RNA 2016 unaltered or reduced affinity of modified analogs
18 classic SELEX derived GTP binding RNA aptamers Class I G31 GTP G Class III K d = 76 nm K d = 30 nm K d = 300 nm K d = 300 nm K d = 8000 nm Class II Class IV K d =250 nm K d = 300 nm K d =400 nm K d = 900 nm 9-4 K d = 9 nm Class V K d = 17 nm GTP Davis and Szostak, PNAS 2002; Carothers et al., JACS 2004; Carothers et al., JACS 2006; Carothers et al, RNA 2006; Nasiri et al, RNA 2016
19 classic SELEX derived GTP binding RNA aptamers Class I G31 GTP G Class III K d = 76 nm K d = 30 nm K d = 300 nm K d = 300 nm K d = 8000 nm Class II Class IV K d =250 nm K d = 300 nm K d =400 nm K d = 900 nm 9-4 K d = 9 nm Class V K d = 17 nm GTP Davis and Szostak, PNAS 2002; Carothers et al., JACS 2004; Carothers et al., JACS 2006; Carothers et al, RNA 2006; Nasiri et al, RNA 2016
20 GTP class II aptamer 1 H-1D G U GTP Wolter et al., Angew. Chem. Int. Ed. 2017
21 NMR solution structure GTP class II Wolter et al., Angew. Chem. Int. Ed. 2017
22 Backbone topology and trans A8:A27 base pair Wolter et al., Angew. Chem. Int. Ed. 2017
23 A8:A27 base pair in a lr-hnn-cosy 13 C 15 N-adenine labeled RNA 293 K lr-hnn-cosy HNN-COSY scalar coupling across H-N N type H-bonds in RNA G C Wolter et al., Angew. Chem. Int. Ed. 2017
24 Isosteric replacement with G8:G27 base pair WT unlabeled RNA, A8GA27G unlabeled RNA 293 K C1 -C1 distance 13.5 Å 1 H, 1 H-NOESY Wolter et al., Angew. Chem. Int. Ed C1 -C1 distance 13.4 Å
25 Inter- and intramolecular base triplets NH 2 -HNN-COSY Wolter et al., Angew. Chem. Int. Ed. 2017
26 ! GTP is recognized through Watson-Crick base pairing with C17! A22 recognizes the sugar edge of GTP! 2 OH-group of GTP also forms a hydrogen bond to A20! 5 -triphosphate group is not recognized Novel GTP recognition mode Wolter et al., Angew. Chem. Int. Ed. 2017
27 A unique base quadruplet with a protonated adenine 13 C 15 N-adenine labeled RNA 293 K 1 H-1D 1 H, 15 N-HSQC imine tautomer Wolter et al., Angew. Chem. Int. Ed. 2017
28 A unique base quadruplet with a protonated adenine 13 C 15 N-adenine labeled RNA 293 K 1 H-1D 1 H, 15 N-HSQC imine tautomer X Wolter et al., Angew. Chem. Int. Ed. 2017
29 A unique base quadruplet with a protonated adenine 13 C 15 N-adenine labeled RNA 293 K 1 H-1D 1 H, 15 N-HSQC imine tautomer N1 protonated adenine X H(N)C Wolter et al., Angew. Chem. Int. Ed. 2017
30 A unique base quadruplet with a protonated adenine 15 N labeled RNA 293 K HNN-COSY Wolter et al., Angew. Chem. Int. Ed HNN-COSY scalar coupling across H-N N type H-bonds in RNA G C
31 A unique base quadruplet with a protonated adenine 15 N labeled RNA 293 K lr- 1 H, 15 N-HSQC HNN-COSY Wolter et al., Angew. Chem. Int. Ed. 2017
32 A unique base quadruplet with a protonated adenine 15 N labeled RNA 293 K lr- 1 H, 15 N-HSQC HNN-COSY 13 C, 15 N-guanine/uridine labeled RNA 293 K H(N)C Wolter et al., Angew. Chem. Int. Ed. 2017
33 A unique base quadruplet with a protonated adenine 1 H-1D 13 C, 15 N-guanine/uridine labeled RNA 293 K lr- 1 H, 31 P-HSQC Wolter et al., Angew. Chem. Int. Ed. 2017; Duchardt et al., Angew. Chem. Int. Ed. 2011
34 A unique base quadruplet with a protonated adenine Wolter et al., Angew. Chem. Int. Ed. 2017
35 Previous examples for protonated nucleotides pk a ~ 3.5 pk a ~ 4.2 catalysis structural transitions conformational equilibria structural adenines pk a cytidines pk a leadzyme hairpin ribozyme domain A, B Neurospora VS ribozyme U6 RNA ISL (spliceosome) VS ribozyme HIV dimer initiation site , > frameshifting pseudoknots Murine leukemia virus 6.2 HDV ribozyme 6.4 frameshifting pseudoknots Beet western yellows virus Pea enation mosaic virus C + GC(A) hww A(+)C WW C+C tww Wolter et al., Angew. Chem. Int. Ed. 2017
36 A stably protonated adenine ph 8.3 ph 6.3 unusual stability at high temperature high ph 1 H, 13 C-HSQC unusual high pk a 1 H-1D 293K ph 8.3 ph 6.3 ph 6.3 Wolter et al., Angew. Chem. Int. Ed. 2017
37 pk a for protonation of A11 in complex ph 5.8 ph 6.3 ph 8.3 K d = 0.7 µm K d = 1.0 µm K d = 19.8 µm K B = ph independent intrinsic binding constant pk af = pk a free pk ab = pk a bound A11 in complex pk a = 8.9 lower limit free adenosine pk a = 3.5 Wolter et al., Angew. Chem. Int. Ed. 2017; Xie, Biochemistry 1997 courtesy of Katharina Weickhmann
38 pk a for protonation of A11 in free RNA ph 5.8 ph 6.3 ph 8.3 K d = 0.7 µm K d = 1.0 µm K d = 19.8 µm K B = ph independent intrinsic binding constant pk af = pk a free pk ab = pk a bound A11 in free RNA free adenosine pk a = 6.7 pk a = 3.5 Wolter et al., Angew. Chem. Int. Ed. 2017; Xie, Biochemistry 1997 courtesy of Katharina Weickhmann
39 RNA is prefolded without ligand at low ph ph mm Mg 2+ ph mm Mg 2+ + GTP 13 C 15 N-adenine labeled RNA 293 K 1 H, 13 C-HSQC Wolter et al., Angew. Chem. Int. Ed. 2017
40 Free RNA is a conformational mixture at ph 6.3 ph mm Mg C 15 N-adenine labeled RNA 293 K 1 H, 13 C-HSQC ph mm Mg 2+ ligand binding by conformational capture Wolter et al., Angew. Chem. Int. Ed. 2017
41 Conclusions GTP class II aptamer small RNA aptamer with a surprisingly complex tertiary structure novel mode of ligand recognition, different from other aptamers very stable protonation of adenine required for structural integrity of the aptamer fold most excessively shifted pk a for any adenine reported so far NMR is an ideal tool for disentangling the intricate hydrogen bonding patterns in RNA
42 Thanks to Goethe Uni Frankfurt: AK Wöhnert Elke Duchardt-Ferner Katharina Weickhmann Amir Nasiri Katharina Hantke Heiko Keller Jens Wöhnert Universität Innsbruck: Christoph Kreutz Christoph Wunderlich FLI Jena: Oliver Ohlenschläger AK Güntert Peter Güntert Daniel Gottstein Sina Kazemi and you for your attention!
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