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Fig. 4 | BMC Genomics

Fig. 4

From: Corrupted DNA-binding specificity and ectopic transcription underpin dominant neomorphic mutations in KLF/SP transcription factors

Fig. 4

KLF1-E339K binds to the G-rich strand when purines are present at the fifth position, but lysine residue makes no contact with DNA. a Schematic of how KLF1 binds to CACCC-box motif via the G-rich strand. K = T/G, Y = T/C, M = A/C, R = A/G, N = any nucleotide. The panels in B-E focus on the interaction between the central triplet and ZF2. b Binding mode of the second zinc finger of KLF1 to a central GTG triplet on the G-rich strand, modeled on the crystal structure of KLF4 bound to the cognate GTG-containing DNA (PDB ID 5ke6). A weak C-H···O bond is the only contact between the glutamate (E) at the + 3 position and the central DNA base (T5). c Binding mode of the second zinc finger of KLF1 to a central GCG triplet on the G-rich strand, modeled on the crystal structure of KLF4 bound to the cognate GCG-containing DNA (PDB ID 2wbu). The glutamate does not directly contact the DNA but instead hydrogen bonds to the arginine (R) at the − 1 position. d Proposed binding mode of second zinc finger of KLF1-E339K to a central GGG triplet on the G-rich strand. The larger, positively charged lysine (K) sidechain extends towards the DNA and is able to act as a hydrogen bond donor, contacting the carbonyl group on G5 and forming a favorable hydrogen bond (shown in gold). e Proposed binding mode of second zinc finger of KLF1-E339K to a central GAG triplet on the G-rich strand. Substitution of guanine for adenine removes the hydrogen bond acceptor but an alternative, hydrogen bond is possible with the N7 atom of the adenine ring (shown in gold). This arrangement may also be possible when the central nucleotide is a G, however it is predicted that the N-H···O bond shown in D) is preferred, leading to a comparatively stronger affinity for GGG over GAG

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