3OMJ

Structural Basis for Cyclic Py-Im Polyamide Allosteric Inhibition of Nuclear Receptor Binding

Summary for 3OMJ

• Entry DOI: 10.2210/pdb3omj/pdb
• Descriptor: 5'-D(*CP*(C38)P*AP*GP*TP*AP*CP*TP*GP*G)-3', CALCIUM ION, (23R,52R)-23,52-diamino-5,11,17,28,34,40,46,57-octamethyl-2,5,8,11,14,17,20,25,28,31,34,37,40,43,46,49,54,57,60,64-icosaazanonacyclo[54.2.1.1~4,7~.1~10,13~.1~16,19~.1~27,30~.1~33,36~.1~39,42~.1~45,48~]hexahexaconta-1(58),4(66),6,10(65),12,16(64),18,27(63),29,33(62),35,39(61),41,45(60),47,56(59)-hexadecaene-3,9,15,21,26,32,38,44,50,55-decone, ... (4 entities in total)
• Functional Keywords: cyclic py-im polyamide, dna
• Total number of polymer chains: 2
• Total formula weight: 7681.33

Authors

Chenoweth, D.M. (deposition date: 2010-08-27, release date: 2010-09-08, Last modification date: 2024-02-21)

Primary citation

Chenoweth, D.M.,Dervan, P.B.
Structural basis for cyclic py-im polyamide allosteric inhibition of nuclear receptor binding.
J.Am.Chem.Soc., 132:14521-14529, 2010

PubMed Abstract: Pyrrole-imidazole polyamides are a class of small molecules that can be programmed to bind a broad repertoire of DNA sequences, disrupt transcription factor-DNA interfaces, and modulate gene expression pathways in cell culture experiments. In this paper we describe a high-resolution X-ray crystal structure of a β-amino turn-linked eight-ring cyclic Py-Im polyamide bound to the central six base pairs of the sequence d(5'-CCAGTACTGG-3')(2), revealing significant modulation of DNA shape. We compare the DNA structural perturbations induced by DNA-binding transcripton factors, androgen receptor and glucocorticoid receptor, in the major groove to those induced by cyclic polyamide binding in the minor groove. The cyclic polyamide is an allosteric modulator that perturbs the DNA structure in such a way that nuclear receptor protein binding is no longer compatible. This allosteric perturbation of the DNA helix provides a molecular basis for disruption of transcription factor-DNA interfaces by small molecules, a minimum step in chemical control of gene networks.

PubMed: 20812704
DOI: 10.1021/ja105068b

Experimental method

X-RAY DIFFRACTION (0.95 Å)