6V0L

PDGFR-b Promoter Forms a G-Vacancy Quadruplex that Can be Complemented by dGMP: Molecular Structure and Recognition of Guanine Derivatives and Metabolites

Summary for 6V0L

• Entry DOI: 10.2210/pdb6v0l/pdb
• NMR Information: BMRB: 30688
• Descriptor: DNA (5'-D(*(3D1)P*AP*GP*GP*GP*AP*GP*GP*GP*CP*GP*GP*CP*GP*GP*GP*AP*CP*A)-3'), 2'-DEOXYGUANOSINE-5'-MONOPHOSPHATE (2 entities in total)
• Functional Keywords: g-quadruplex, pdgfr-b, promoter, dna
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 6277.13

Authors

Wang, K.B.,Dickerhoff, J.,Wu, G.,Yang, D. (deposition date: 2019-11-18, release date: 2020-03-11, Last modification date: 2024-05-01)

Primary citation

Wang, K.B.,Dickerhoff, J.,Wu, G.,Yang, D.
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, 2020

PubMed 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.

PubMed: 32101424
DOI: 10.1021/jacs.9b12770

Experimental method

SOLUTION NMR