Summary information

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. doi: 10.1093/nar/gkr522.
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

Base-block schematics in six views

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List of 2 G-tetrads

 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

List of 1 G4-helix

In DSSR, a G4-helix is defined by stacking interactions of G-tetrads, regardless of backbone connectivity, and may contain more than one G4-stem.

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

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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

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List of 1 G4-stem

In DSSR, a G4-stem is defined as a G4-helix with backbone connectivity. Bulges are also allowed along each of the four strands.

Stem#1, 2 G-tetrad layers, 2 loops, INTRA-molecular, DDUD, hybrid-(mixed), 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

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