Summary information and primary citation

PDB-id
9c46
Class
DNA
Method
X-ray (2.39 Å)
Summary
Right-left hybrid parallel g-quadruplex from slc2a1 promoter
Reference
Seth P, Xing E, Hendrickson AD, Li K, Monsen R, Chaires JB, Neidle S, Yatsunyk LA (2025): "Interaction of N-methylmesoporphyrin IX with a hybrid left-/right-handed G-quadruplex motif from the promoter of the SLC2A1 gene." Nucleic Acids Res., 53. doi: 10.1093/nar/gkae1208.
Abstract
Left-handed G-quadruplexes (LHG4s) belong to a class of recently discovered noncanonical DNA structures under the larger umbrella of G-quadruplex DNAs (G4s). The biological relevance of these structures and their ability to be targeted with classical G4 ligands is underexplored. Here, we explore whether the putative LHG4 DNA sequence from the SLC2A1 oncogene promoter maintains its left-handed characteristics upon addition of nucleotides in the 5'- and 3'-direction from its genomic context. We also investigate whether this sequence interacts with a well-established G4 binder, N-methylmesoporphyrin IX (NMM). We employed biophysical and X-ray structural studies to address these questions. Our results indicate that the sequence d[G(TGG)3TGA(TGG)4] (termed here as SLC) adopts a two-subunit, four-tetrad hybrid left-/right-handed G4 (LH/RHG4) topology. Addition of 5'-G or 5'-GG abolishes the left-handed fold in one subunit, while the addition of 3'-C or 3'-CA maintains the original fold. X-ray crystal structure analyses show that SLC maintains the same hybrid LH/RHG4 fold in the solid state and that NMM stacks onto the right-handed subunit of SLC. NMM binds to SLC with a 1:1 stoichiometry and a moderate-to-tight binding constant of 15 μM-1. This work deepens our understanding of LHG4 structures and their binding with traditional G4 ligands.
G4 notes
4 G-tetrads, 1 G4 helix, 1 G4 stem, UUUU, parallel, 4+0, 2(-P-P-P)

Cartoon-block schematics in six views (download the tarball)

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List of 4 G-tetrads

 1 glyco-bond=---- sugar=---- groove=---- planarity=0.104 type=planar O+ nts=4 GGGG A.DG1,A.DG4,A.DG7,A.DG10
 2 glyco-bond=---- sugar=---- groove=---- planarity=0.207 type=other  O+ nts=4 GGGG A.DG3,A.DG6,A.DG9,A.DG12
 3 glyco-bond=---- sugar=---- groove=---- planarity=0.058 type=planar O+ nts=4 GGGG A.DG15,A.DG18,A.DG21,A.DG24
 4 glyco-bond=---- sugar=---- groove=---- planarity=0.131 type=planar O+ nts=4 GGGG A.DG16,A.DG19,A.DG22,A.DG25

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, 4 G-tetrads, INTRA-molecular, with 1 stem
 1  glyco-bond=---- sugar=---- groove=---- WC-->Major O+ nts=4 GGGG A.DG3,A.DG6,A.DG9,A.DG12
 2  glyco-bond=---- sugar=---- groove=---- WC-->Major O+ nts=4 GGGG A.DG4,A.DG7,A.DG10,A.DG1
 3  glyco-bond=---- sugar=---- groove=---- Major-->WC O+ nts=4 GGGG A.DG21,A.DG18,A.DG15,A.DG24
 4  glyco-bond=---- sugar=---- groove=---- Major-->WC O+ nts=4 GGGG A.DG22,A.DG19,A.DG16,A.DG25
  step#1  mp(<<,backward) area=11.26 rise=3.27 twist=-25.9
  step#2  mm(<>,outward)  area=29.24 rise=3.32 twist=-11.3
  step#3  pm(>>,forward)  area=8.83  rise=3.19 twist=35.7
  strand#1 DNA glyco-bond=---- sugar=---- nts=4 GGGG A.DG3,A.DG4,A.DG21,A.DG22
  strand#2 DNA glyco-bond=---- sugar=---- nts=4 GGGG A.DG6,A.DG7,A.DG18,A.DG19
  strand#3 DNA glyco-bond=---- sugar=---- nts=4 GGGG A.DG9,A.DG10,A.DG15,A.DG16
  strand#4 DNA glyco-bond=---- sugar=---- nts=4 GGGG A.DG12,A.DG1,A.DG24,A.DG25

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3 stacking diagrams 
 1  glyco-bond=---- sugar=---- groove=---- WC-->Major O+ nts=4 GGGG A.DG3,A.DG6,A.DG9,A.DG12
 2  glyco-bond=---- sugar=---- groove=---- WC-->Major O+ nts=4 GGGG A.DG4,A.DG7,A.DG10,A.DG1
  step#1  mp(<<,backward) area=11.26 rise=3.27 twist=-25.9

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 2  glyco-bond=---- sugar=---- groove=---- WC-->Major O+ nts=4 GGGG A.DG4,A.DG7,A.DG10,A.DG1
 3  glyco-bond=---- sugar=---- groove=---- Major-->WC O+ nts=4 GGGG A.DG21,A.DG18,A.DG15,A.DG24
  step#2  mm(<>,outward)  area=29.24 rise=3.32 twist=-11.3

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 3  glyco-bond=---- sugar=---- groove=---- Major-->WC O+ nts=4 GGGG A.DG21,A.DG18,A.DG15,A.DG24
 4  glyco-bond=---- sugar=---- groove=---- Major-->WC O+ nts=4 GGGG A.DG22,A.DG19,A.DG16,A.DG25
  step#3  pm(>>,forward)  area=8.83  rise=3.19 twist=35.7

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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-tetrads, 3 loops, INTRA-molecular, UUUU, parallel, 4+0, 2(-P-P-P)
 1  glyco-bond=---- sugar=---- groove=---- WC-->Major O+ nts=4 GGGG A.DG15,A.DG18,A.DG21,A.DG24
 2  glyco-bond=---- sugar=---- groove=---- WC-->Major O+ nts=4 GGGG A.DG16,A.DG19,A.DG22,A.DG25
  step#1  pm(>>,forward)  area=8.83  rise=3.19 twist=35.7
  strand#1  U DNA glyco-bond=-- sugar=-- nts=2 GG A.DG15,A.DG16
  strand#2  U DNA glyco-bond=-- sugar=-- nts=2 GG A.DG18,A.DG19
  strand#3  U DNA glyco-bond=-- sugar=-- nts=2 GG A.DG21,A.DG22
  strand#4  U DNA glyco-bond=-- sugar=-- nts=2 GG A.DG24,A.DG25
  loop#1 type=propeller strands=[#1,#2] nts=1 T A.DT17
  loop#2 type=propeller strands=[#2,#3] nts=1 T A.DT20
  loop#3 type=propeller strands=[#3,#4] nts=1 T A.DT23

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List of 2 non-stem G4-loops (including the two closing Gs)

 1 type=V-shaped  helix=#1 nts=4 GTGG A.DG1,A.DT2,A.DG3,A.DG4
 2* type=V-shaped  helix=#1 nts=4 GGTG A.DG9,A.DG10,A.DT11,A.DG12