DSSR-derived G-quadruplex features in PDB entry 3qlp

PDB-id

3qlp

Class

hydrolase-hydrolase inhibitor-DNA

Method

X-ray (2.14 Å)

Summary

X-ray structure of the complex between human alpha thrombin and a modified thrombin binding aptamer (mtba)

Reference

Russo Krauss, I., Merlino, A., Giancola, C., Randazzo, A., Mazzarella, L., Sica, F.: (2011) "Thrombin-aptamer recognition: a revealed ambiguity." Nucleic Acids Res., 39, 7858-7867.

Abstract

Aptamers are structured oligonucleotides that recognize molecular targets and can function as direct protein inhibitors. The best-known example is the thrombin-binding aptamer, TBA, a single-stranded 15-mer DNA that inhibits the activity of thrombin, the key enzyme of coagulation cascade. TBA folds as a G-quadruplex structure, as proved by its NMR structure. The X-ray structure of the complex between TBA and human α-thrombin was solved at 2.9-Å resolution, but did not provide details of the aptamer conformation and the interactions with the protein molecule. TBA is rapidly processed by nucleases. To improve the properties of TBA, a number of modified analogs have been produced. In particular, a modified TBA containing a 5'-5' polarity inversion site, mTBA, has higher stability and higher affinity toward thrombin with respect to TBA, although it has a lower inhibitory activity. We present the crystal structure of the thrombin-mTBA complex at 2.15-Å resolution; the resulting model eventually provides a clear picture of thrombin-aptamers interaction, and also highlights the structural bases of the different properties of TBA and mTBA. Our findings open the way for a rational design of modified aptamers with improved potency as anticoagulant drugs.

G4 notes

2 G-tetrads, 1 G4 helix, 1 G4 stem · 2(-Lw-Ln), UD3(1+3), DDUD

 1 glyco-bond=--s- groove=-wn- planarity=0.267 type=other  nts=4 GGGG D.DG1,D.DG6,D.DG10,D.DG15
 2 glyco-bond=ss-s groove=-wn- planarity=0.236 type=other  nts=4 GGGG D.DG2,D.DG5,D.DG11,D.DG14

Helix#1, 2 G-tetrad layers, INTRA-molecular, with 1 stem

	1 glyco-bond=--s- groove=-wn- WC-->Major nts=4 GGGG D.DG1,D.DG6,D.DG10,D.DG15 2 glyco-bond=ss-s groove=-wn- Major-->WC nts=4 GGGG D.DG2,D.DG5,D.DG11,D.DG14 step#1 mm(<>,outward) area=16.30 rise=3.45 twist=15.6 strand#1 DNA glyco-bond=-s nts=2 GG D.DG1,D.DG2 strand#2 DNA glyco-bond=-s nts=2 GG D.DG6,D.DG5 strand#3 DNA glyco-bond=s- nts=2 GG D.DG10,D.DG11 strand#4 DNA glyco-bond=-s nts=2 GG D.DG15,D.DG14 Download PDB file Interactive view in 3Dmol.js
1 stacking diagram
	1 glyco-bond=--s- groove=-wn- WC-->Major nts=4 GGGG D.DG1,D.DG6,D.DG10,D.DG15 2 glyco-bond=ss-s groove=-wn- Major-->WC nts=4 GGGG D.DG2,D.DG5,D.DG11,D.DG14 step#1 mm(<>,outward) area=16.30 rise=3.45 twist=15.6 Download PDB file Interactive view in 3Dmol.js

Stem#1, 2 G-tetrad layers, 2 loops, INTRA-molecular, DDUD, anti-parallel, 2(-Lw-Ln), UD3(1+3)

1 glyco-bond=--s- groove=-wn- WC-->Major nts=4 GGGG D.DG1,D.DG6,D.DG10,D.DG15 2 glyco-bond=ss-s groove=-wn- Major-->WC nts=4 GGGG D.DG2,D.DG5,D.DG11,D.DG14 step#1 mm(<>,outward) area=16.30 rise=3.45 twist=15.6 strand#1 D DNA glyco-bond=-s nts=2 GG D.DG1,D.DG2 strand#2 D DNA glyco-bond=-s nts=2 GG D.DG6,D.DG5 strand#3 U DNA glyco-bond=s- nts=2 GG D.DG10,D.DG11 strand#4 D DNA glyco-bond=-s nts=2 GG D.DG15,D.DG14 loop#1 type=lateral strands=[#2,#3] nts=3 TGT D.DT7,D.DG8,D.DT9 loop#2 type=lateral strands=[#3,#4] nts=2 TT D.DT12,D.DT13 Download PDB file Interactive view in 3Dmol.js