This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.

1nzm

From Proteopedia

(Difference between revisions)

Jump to: navigation, search

Revision as of 10:04, 1 November 2017

NMR structure of the parallel-stranded DNA quadruplex d(TTAGGGT)4 complexed with the telomerase inhibitor RHPS4

Structural highlights

1nzm is a 4 chain structure. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	1np9
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

The NMR structure of the parallel-stranded DNA quadruplex d(TTAGGGT)(4), containing the human telomeric repeat, has been determined in solution in complex with a fluorinated pentacyclic quino[4,3,2-kl]acridinium cation (RHPS4). RHPS4 has been identified as a potent inhibitor of telomerase at submicromolar levels (IC(50) value of 0.33(+/-0.13)microM), exhibiting a wide differential between telomerase inhibition and acute cellular toxicity. All of the data point to RHPS4 exerting its chemotherapeutic potency through interaction with, and stabilisation of, four-stranded G-quadruplex structures. RHPS4 forms a dynamic interaction with d(TTAGGGT)(4), as evident from 1H and 19F linewidths, with fast exchange between binding sites induced at 318 K. Perturbations to DNA chemical shifts and 24 intermolecular nuclear Overhauser effects (NOEs) identify the 5'-ApG and 5'-GpT steps as the principle intercalation sites; a structural model has been refined using NOE-restrained molecular dynamics. The central G-tetrad core remains intact, with drug molecules stacking at the ends of the G-quadruplex. The partial positive charge on position 13-N of the acridine ring appears to act as a "pseudo" potassium ion and is positioned above the centre of the G-tetrad in the region of high negative charge density. In both ApG and GpT intercalation sites, the drug is seen to converge to the same orientation in which the pi-system of the drug overlaps primarily with two bases of each G-tetrad. The drug is held in place by stacking interactions with the G-tetrads; however, there is some evidence for a more dynamic, weakly stabilised A-tetrad that stacks partially on top of the drug at the 5'-end of the sequence. Together, the interactions of RHPS4 increase the t(m) of the quadruplex by approximately 20 degrees C. There is no evidence for drug intercalation within the G-quadruplex; however, the structural model strongly supports end-stacking interactions with the terminal G-tetrads.

Drug recognition and stabilisation of the parallel-stranded DNA quadruplex d(TTAGGGT)4 containing the human telomeric repeat.,Gavathiotis E, Heald RA, Stevens MF, Searle MS J Mol Biol. 2003 Nov 14;334(1):25-36. PMID:14596797^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Gavathiotis E, Heald RA, Stevens MF, Searle MS. Drug recognition and stabilisation of the parallel-stranded DNA quadruplex d(TTAGGGT)4 containing the human telomeric repeat. J Mol Biol. 2003 Nov 14;334(1):25-36. PMID:14596797

1 Structural highlights
2 Publication Abstract from PubMed
3 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1nzm"

@@ Line 1: / Line 1: @@
 ==NMR structure of the parallel-stranded DNA quadruplex d(TTAGGGT)4 complexed with the telomerase inhibitor RHPS4==
 <StructureSection load='1nzm' size='340' side='right' caption='[[1nzm]], [[NMR_Ensembles_of_Models | 10 NMR models]]' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=LG1:3,11-DIFLUORO-6,8,13-TRIMETHYL-8H-QUINO[4,3,2-KL]ACRIDIN-13-IUM'>LG1</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1np9|1np9]]</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1nzm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1nzm OCA], [http://pdbe.org/1nzm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1nzm RCSB], [http://www.ebi.ac.uk/pdbsum/1nzm PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1nzm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1nzm OCA], [http://pdbe.org/1nzm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1nzm RCSB], [http://www.ebi.ac.uk/pdbsum/1nzm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1nzm ProSAT]</span></td></tr>
 </table>
 <div style="background-color:#fffaf0;">

1nzm

From Proteopedia

Revision as of 10:04, 1 November 2017

NMR structure of the parallel-stranded DNA quadruplex d(TTAGGGT)4 complexed with the telomerase inhibitor RHPS4

Structural highlights

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox