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PDB-id
6v0l
Class
DNA
Method
NMR
Summary
Pdgfr-b promoter forms a g-vacancy quadruplex that can be complemented by dgmp: molecular structure and recognition of guanine derivatives and metabolites
Reference
Wang, K.B., Dickerhoff, J., Wu, G., Yang, D.: (2020) "PDGFR-beta Promoter Forms a Vacancy G-Quadruplex that Can Be Filled in by dGMP: Solution Structure and Molecular Recognition of Guanine Metabolites and Drugs." J.Am.Chem.Soc., 142, 5204-5211.
Abstract
Aberrant expression of PDGFR-β is associated with a number of diseases. The G-quadruplexes (G4s) formed in PDGFR-β gene promoter are transcriptional modulators and amenable to small molecule targeting. The major G4 formed in the PDGFR-β gene promoter was previously shown to have a broken G-strand. Herein, we report that the PDGFR-β gene promoter sequence forms a vacancy G-quadruplex (vG4) which can be filled in and stabilized by physiologically relevant guanine metabolites, such as dGMP, GMP, and cGMP, as well as guanine-derivative drugs. We determined the NMR structure of the dGMP-fill-in PDGFR-β vG4 in K+ solution. This is the first structure of a guanine-metabolite-fill-in vG4 based on a human gene promoter sequence. Our structure and systematic analysis elucidate the contributions of Hoogsten hydrogen bonds, sugar, and phosphate moieties to the specific G-vacancy fill-in. Intriguingly, an equilibrium of 3'- and 5'-end vG4s is present in the PDGFR-β promoter sequence, and dGMP favors the 5'-end fill-in. Guanine metabolites and drugs were tested and showed a conserved selectivity for the 5'-vacancy, except for cGMP. cGMP binds both the 3'- and 5'-end vG4s and forms two fill-in G4s with similar population. Significantly, guanine metabolites are involved in many physiological and pathological processes in human cells; thus, our results provide a structural basis to understand their potential regulatory functions by interaction with promoter vG4s. Moreover, the NMR structure can guide rational design of ligands that target the PDGFR-β vG4.
G4 notes
3 G-tetrads, 1 G4 helix, 1 G4 stem · 2(-P-P-P), parallel(4+0), UUUU

Base-block schematics in six views [summary · tetrads · helices · stems · costacks · homepage]

PyMOL session file PDB file View in 3Dmol.js

List of 3 G-tetrads [summary · schematics · helices · stems · costacks · homepage]

 1 glyco-bond=---- groove=---- planarity=0.480 type=other  nts=4 GGgG X.DG3,X.DG7,X.DGP101,X.DG14
 2 glyco-bond=---- groove=---- planarity=0.296 type=bowl-2 nts=4 GGGG X.DG4,X.DG8,X.DG11,X.DG15
 3 glyco-bond=---- groove=---- planarity=0.344 type=bowl   nts=4 GGGG X.DG5,X.DG9,X.DG12,X.DG16

List of 1 G4-helix [summary · schematics · tetrads · stems · costacks · homepage]

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, 3 G-tetrad layers, INTRA-molecular, with 1 stem

 1  glyco-bond=---- groove=---- WC-->Major nts=4 GGgG X.DG3,X.DG7,X.DGP101,X.DG14
 2  glyco-bond=---- groove=---- WC-->Major nts=4 GGGG X.DG4,X.DG8,X.DG11,X.DG15
 3  glyco-bond=---- groove=---- WC-->Major nts=4 GGGG X.DG5,X.DG9,X.DG12,X.DG16
  step#1  pm(>>,forward)  area=16.08 rise=3.47 twist=21.5
  step#2  pm(>>,forward)  area=13.01 rise=3.52 twist=26.4
  strand#1 DNA glyco-bond=--- nts=3 GGG X.DG3,X.DG4,X.DG5
  strand#2 DNA glyco-bond=--- nts=3 GGG X.DG7,X.DG8,X.DG9
  strand#3 DNA glyco-bond=--- nts=3 gGG X.DGP101,X.DG11,X.DG12
  strand#4 DNA glyco-bond=--- nts=3 GGG X.DG14,X.DG15,X.DG16

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2 stacking diagrams
 1  glyco-bond=---- groove=---- WC-->Major nts=4 GGgG X.DG3,X.DG7,X.DGP101,X.DG14
2 glyco-bond=---- groove=---- WC-->Major nts=4 GGGG X.DG4,X.DG8,X.DG11,X.DG15
step#1 pm(>>,forward) area=16.08 rise=3.47 twist=21.5

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 2  glyco-bond=---- groove=---- WC-->Major nts=4 GGGG X.DG4,X.DG8,X.DG11,X.DG15
3 glyco-bond=---- groove=---- WC-->Major nts=4 GGGG X.DG5,X.DG9,X.DG12,X.DG16
step#2 pm(>>,forward) area=13.01 rise=3.52 twist=26.4

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List of 1 G4-stem [summary · schematics · tetrads · helices · costacks · homepage]

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, 3 loops, INTRA-molecular, UUUU, parallel, 2(-P-P-P), parallel(4+0)

 1  glyco-bond=---- groove=---- WC-->Major nts=4 GGGG X.DG4,X.DG8,X.DG11,X.DG15
 2  glyco-bond=---- groove=---- WC-->Major nts=4 GGGG X.DG5,X.DG9,X.DG12,X.DG16
  step#1  pm(>>,forward)  area=13.01 rise=3.52 twist=26.4
  strand#1  U DNA glyco-bond=-- nts=2 GG X.DG4,X.DG5
  strand#2  U DNA glyco-bond=-- nts=2 GG X.DG8,X.DG9
  strand#3  U DNA glyco-bond=-- nts=2 GG X.DG11,X.DG12
  strand#4  U DNA glyco-bond=-- nts=2 GG X.DG15,X.DG16
  loop#1 type=propeller strands=[#1,#2] nts=2 AG X.DA6,X.DG7
  loop#2 type=propeller strands=[#2,#3] nts=1 C X.DC10
  loop#3 type=propeller strands=[#3,#4] nts=2 CG X.DC13,X.DG14

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List of 0 G4 coaxial stacks [summary · schematics · tetrads · helices · stems · homepage]

List of 0 non-stem G4-loops (including the two closing Gs)