1RMX

A SHORT LEXITROPSIN THAT RECOGNIZES THE DNA MINOR GROOVE AT 5'-ACTAGT-3': UNDERSTANDING THE ROLE OF ISOPROPYL-THIAZOLE

Summary for 1RMX

• Entry DOI: 10.2210/pdb1rmx/pdb
• Related: 1RN9
• Descriptor: 5'-D(*CP*GP*AP*CP*TP*AP*GP*TP*CP*G)-3', N-[3-(DIMETHYLAMINO)PROPYL]-2-({[4-({[4-(FORMYLAMINO)-1-METHYL-1H-PYRROL-2-YL]CARBONYL}AMINO)-1-METHYL-1H-PYRROL-2-YL]CARBONYL}AMINO)-5-ISOPROPYL-1,3-THIAZOLE-4-CARBOXAMIDE (2 entities in total)
• Functional Keywords: minor-groove-dna complex, side-by-side binding, dna recognition, dna
• Total number of polymer chains: 2
• Total formula weight: 7175.32

Authors

Anthony, N.G.,Johnston, B.F.,Khalaf, A.I.,Mackay, S.P.,Parkinson, J.A.,Suckling, C.J.,Waigh, R.D. (deposition date: 2003-11-28, release date: 2004-08-24, Last modification date: 2024-05-22)

Primary citation

Anthony, N.G.,Johnston, B.F.,Khalaf, A.I.,MacKay, S.P.,Parkinson, J.A.,Suckling, C.J.,Waigh, R.D.
Short Lexitropsin that Recognizes the DNA Minor Groove at 5'-ACTAGT-3': Understanding the Role of Isopropyl-thiazole.
J.Am.Chem.Soc., 126:11338-11349, 2004

PubMed Abstract: Isopropyl-thiazole ((iPr)Th) represents a new addition to the building blocks of nucleic acid minor groove-binding molecules. The DNA decamer duplex d(CGACTAGTCG)(2) is bound by a short lexitropsin of sequence formyl-PyPy(iPr)Th-Dp (where Py represents N-methyl pyrrole, (iPr)Th represents thiazole with an isopropyl group attached, and Dp represents dimethylaminopropyl). NMR data indicate ligand binding in the minor groove of DNA to the sequence 5'-ACT(5)AG(7)T-3' at a 2:1 ratio of ligand to DNA duplex. Ligand binding, assisted by the enhanced hydrophobicity of the (iPr)Th group, occurs in a head-to-tail fashion, the formyl headgroups being located toward the 5'-ends of the DNA sequence. Sequence reading is augmented through hydrogen bond formation between the exocyclic amine protons of G(7) and the (iPr)Th nitrogen, which lies on the minor groove floor. The B(I)/B(II) DNA backbone equilibrium is altered at the T(5) 3'-phosphate position to accommodate a B(II) configuration. The ligands bind in a staggered mode with respect to one another creating a six base pair DNA reading frame. The introduction of a new DNA sequence-reading element into the recognition jigsaw, combined with an extended reading frame for a small lexitropsin with enhanced hydrophobicity, holds great promise in the development of new, potentially commercially viable drug lead candidates for gene targeting.

PubMed: 15355117
DOI: 10.1021/ja030658n

Experimental method

SOLUTION NMR