PubMed Health⌕ Search

Biomedical subjects

C M Nunn

Publications and source records attributed to C M Nunn.

At least 19 recordsLinked to original sources
PubMed1999

DNA minor groove recognition of a non-self-complementary AT-rich sequence by a tris-benzimidazole ligand.

The crystal structure of the non-self-complementary dodecamer DNA duplex formed by d(CG[5BrC]ATAT-TTGCG) and d(CGCAAATATGCG) has been solved to 2.3 A resolution, together with that of its complex with the tris-benzimidazole minor groove binding ligand TRIBIZ. The inclusion of a bromine atom on one strand in each structure enabled the possibility of disorder to be discounted. The native structure has an exceptional narrow minor groove, of 2.5-2.6 A in the central part of the A/T region, which is increased in width by approximately 0.8 A on drug binding. The ligand molecule binds in the central part of the sequence. The benzimidazole subunits of the ligand participate in six bifurcated hydrogen bonds with A:T base pair edges, three to each DNA strand. The presence of a pair of C-H...O hydrogen bonds has been deduced from the close proximity of the pyrrolidine group of the ligand to the TpA step in the sequence.

Benzimidazoles↗
PubMed1999

Long-term outcome after primary angioplasty: report from the primary angioplasty in myocardial infarction (PAMI-I) trial.

OBJECTIVES: This study sought to compare the two-year outcome after primary percutaneous coronary angioplasty or thrombolytic therapy for acute myocardial infarction. BACKGROUND: Primary angioplasty, that is, angioplasty without antecedent thrombolytic therapy, has been shown to be an effective reperfusion modality for patients suffering an acute myocardial infarction. This report reviews the two-year clinical outcome of patients randomized in the Primary Angioplasty in Myocardial Infarction trial. METHODS: At 12 clinical centers, 395 patients who presented within 12 h of the onset of myocardial infarction were randomized to undergo primary angioplasty (195 patients) or to receive tissue-type plasminogen activator (t-PA) (200 patients) followed by conservative care. Patients were followed by physician visits, phone call, letter and review of hospital records for any hospital admission at one month, six months, one year and two years. RESULTS: At two years, patients undergoing primary angioplasty had less recurrent ischemia (36.4% vs. 48% for t-PA, p = 0.026), lower reintervention rates (27.2% vs. 46.5% for t-PA, p < 0.0001) and reduced hospital readmission rates (58.5% vs. 69.0% for t-PA, p = 0.035). The combined end point of death or reinfarction was 14.9% for angioplasty versus 23% for t-PA, p = 0.034. Multivariate analysis found angioplasty to be independently predictive of a reduction in death, reinfarction or target vessel revascularization (p = 0.0001). CONCLUSIONS: The initial benefit of primary angioplasty performed by experienced operators is maintained over a two-year follow-up period with improved infarct-free survival and reduced rate of reintervention.

Angioplasty, Balloon, Coronary↗
PubMed1998

Structure of the DNA decamer d(GGCAATTGCG) contains both major- and minor-groove binding G.(G.C) base triplets.

The crystal structure of the decamer d(GGCAATTGCG) has been determined at 2.4 A resolution. The central eight bases of each DNA single-strand base pair with a self-complementary strand to form an octamer B-DNA duplex. These duplexes lie end-to-end within the unit cell. The terminal 5'-G and G-3' bases of each decamer strand are unpaired, and interact with the neighbouring duplexes via interactions within both the major and minor groove. This results in base triplets of the type G-(G.C) and G*(G.C), with the third guanine base binding to a Watson-Crick G.C base pair from the major groove and the minor groove, respectively. The triplet interaction of the type G-(G.C) involves Hoogsteen hydrogen-bonding interactions between the two guanine bases. The minor- and major-groove base triplet interactions which exist within this structure act to stabilize the d(GCAATTGC)2 B-DNA octamer duplex.

Crystallization↗
PubMed1997

A model for the [C+-GxC]n triple helix derived from observation of the C+-GxC base triplet in a crystal structure.

A molecular modelling study on the [C+-GxC]n triple helix is reported. We have observed the C+-GxC base triplet in the crystal structure of an oligonucleotide-drug complex, between the minor-groove drug netropsin and the decanucleotide d(CGCAATTGCG)2. The complex was crystallised at pH 7.0, but the crystal structure, at a resolution of 2.4 A, shows that a terminal cytosine has become protonated and participates in a parallel C+-GxC base triplet. The structure of this triplet and its associated sugar-phosphate backbones have been energy-refined and then used to generate a triple helix. This has characteristics of the B-type family of DNA structures for two strands, with the third, the C+ strand, having backbone conformations closer to the A family.

DNA↗
PubMed1997

Sequence-dependent crossed helix packing in the crystal structure of a B-DNA decamer yields a detailed model for the Holliday junction.

The structure of the B-DNA decamer d(CGCAATTGCG)2 has been determined by X-ray diffraction analysis to a resolution of 2.3 A and an R-factor of 17.7%. The decamer crystallises in the monoclinic space group C2 and packs with a crossed arrangement of helices and a unique crossing contact distinct from all other decamer structures. This is believed to be a direct result of the sequence-dependent minor groove width of the duplex. Crossed helix structures of DNA are valuable starting points for modelling studies of the Holliday junction. Two unique sites are observed at the cross-over junction where strand exchange may occur. A Holliday junction model has been constructed for each case and modelled using molecular mechanics and dynamics techniques. One of these models was found to be fully consistent with the available physical data.

Computer Simulation↗
PubMed1997

Structure of the A-DNA octamer d(GGCATGCC).

The crystal structure of the self-complementary DNA octamer d(GGCATGCC) has been determined to a resolution of 2.38 A and R factor of 17.1%. The structure is an A-DNA octamer duplex with Watson-Crick base pairing along its length. This sequence extends the investigation of octamer duplexes of the type d(GGX(4)CC) which assume P6(1) packing within the crystallographic unit cell. The A-DNA duplex is non-linear with a helix axis curvature of 7 degrees and bending towards the DNA minor groove. In view of the biological importance of protein recognition of some A-DNA sequences the minor-groove geometry and helix-axis curvature for this structure is compared with all others of the type d(GGXATXCC).

Journal Article↗
PubMed1997

Crystal structure of the DNA decamer d(CGCAATTGCG) complexed with the minor groove binding drug netropsin.

The crystal structure of netropsin bound to the decamer d(CGCAATTGCG) has been determined at 2.4 A resolution. This is the first example of a crystal structure of netropsin bound to decamer DNA. The central eight bases of each DNA single-strand base pair with a self-complementary strand to form an octamer B-DNA duplex. These duplexes lie end to end within the unit cell. The terminal 5'-C and G-3' bases are unpaired and interact with the neighboring duplexes via interactions within both the major and minor groove to form base triplet interactions of the type C(+)-G x C and G*(G x C), respectively. The triplet interaction of the type C(+)-G x C is known to exist within triplex DNA with the C+ base oriented parallel with the Watson-Crick guanine base to which it hydrogen bonds. The netropsin molecule lies within the minor groove of the octamer duplex and assumes a class I type position, with bifurcated hydrogen-bonding interactions from the amide groups of the netropsin to the A x T base pairs of the minor groove. The netropsin molecule fits within a five base pair long minor groove site by bending of the flexible amidinium group at one end of the drug.

Anti-Bacterial Agents↗
PubMed1996

A crystallographic and spectroscopic study of the complex between d(CGCGAATTCGCG)2 and 2,5-bis(4-guanylphenyl)furan, an analogue of berenil. Structural origins of enhanced DNA-binding affinity.

2,5-Bis(4-guanylphenyl)furan ("furamidine") is a dicationic minor groove binding drug that has been shown to be more effective than pentamidine against the Pneumocystis carinii pathogen in an immunosuppressed rat model. It has a close structural similarity to the antitrypanosomal drug berenil, differing only on the replacement of the central triazene unit with a furan moiety. we have determined the crystal structure of the complex between furamidine and the DNA dodecamer d(CGCGAATTCGCG)2 and compared it with the same DNA sequence by UV-visible, fluorescence, and CD spectroscopy. Furamidine shows tighter binding to this sequence (Keq = 6.7 x 10(6)) than berenil (Keq = 6.6 x 10(5)). The crystal structure reveals that, unlike berenil, furamidine makes direct hydrogen bond interactions with this DNA sequence through both amidinium groups to O2 atoms of thymine bases and is more isohelical with the minor groove. Molecular mechanics calculations support the hypothesis that these differences result in the improved interaction energy between the ligand and the DNA.

Amidines↗
PubMed1996

The high resolution crystal structure of the DNA decamer d(AGGCATGCCT).

The crystal structure of the DNA decamer d(AGGCATGCCT) has been determined to a resolution of 1.3 A and R factor of 13.9%. The structure has a unique conformation with each of the decamer single strands forming base-pairing interactions with two symmetry-related strands. The central eight bases of the decamer form an A-DNA octamer duplex with one symmetry-related strand whilst the terminal 5'-A and T-3' bases are flipped out and away from the octamer helix axis to form base-pairing interactions with a second symmetry-related strand. These A.T base-pairs lie perpendicular to the crystallographic c axis and pack within the unit cell in conjunction with a symmetry-related A.T base-pair displaced by 3.4 A degrees along the c axis. A novel base triplet interaction of the type A*(G.C) is present in the structure with interaction from the major groove side of the terminal 5'-A base to the minor groove of the central A-DNA octamer. This structure reports the first example of cobalt hexammine binding to a right-handed DNA duplex. The crystallographic asymmetric unit contains two cobalt hexammine ligands with one site in the major groove coordinating via hydrogen bonds to the 5'-AGG bases, and the second site located between DNA molecules and interacting with the oxygen atoms of phosphate groups.

Cobalt↗
PubMed1996

Crystal structure of d(AGGBrCATGCCT): implications for cobalt hexammine binding to DNA.

The crystal structure of the DNA decamer d(AGGBrCATGCCT) has been determined to a resolution of 2.0 A and R factor of 19.6%. Crystals of d(AGGBrCATGCCT) were grown in the presence of cobalt hexammine but no cobalt hexammine ions are bound to the DNA structure. This contrasts with the recently determined crystal structure of d(AGGCATGCCT) which has a similar DNA conformation and cobalt hexammine ions bound directly to the DNA. Comparison with the structure of d(AGGCATGCCT) and appreciation of the crystal packing of this sequence leads to an understanding of how cobalt hexammine binding to DNA occurs and its role in determining DNA conformation.

Antineoplastic Agents↗
PubMed1995

Crystal structure of a DNA decamer showing a novel pseudo four-way helix-helix junction.

The crystal structure of the decanucleotide d(CGCAATTGCG)2 has been solved by a combination of molecular replacement and heavy-atom procedures and has been refined to an R factor of 20.2% at 2.7 A. It is not a fully base-paired duplex but has a central core of eight Watson-Crick base pairs flanked by unpaired terminal guanosines and cytosines. These participate in hydrogen-bonding arrangements with adjacent decamer duplexes in the crystal lattice. The unpaired guanosines are bound in the G+C regions of duplex minor grooves. The cytosines have relatively high mobility, even though they are constrained to be in one region where they are involved in base-paired triplets with G.C base pairs. The 5'-AATT sequence in the duplex region has a narrow minor groove, providing further confirmation of the sequence-dependent nature of groove width.

Base Composition↗
PubMed1995

Variability in DNA minor groove width recognised by ligand binding: the crystal structure of a bis-benzimidazole compound bound to the DNA duplex d(CGCGAATTCGCG)2.

An analogue of the DNA-binding compound Hoechst 33258, in which the piperazine ring has been replaced by an imidazoline group, has been cocrystallized with the dodecanucleotide sequence d(CGCGAATTCGCG)2. The structure has been solved by X-ray diffraction analysis and has been refined to an R-factor of 19.7% at a resolution of 2.0 A. The ligand is found to bind in the minor groove, at the central four AATT base pairs of the B-DNA double helix, with the involvement of a number of van der Waals contacts and hydrogen bonds. There are significant differences in minor groove width for the two compounds, along much of the AATT region. In particular this structure shows a narrower groove at the 3' end of the binding site consistent with the narrower cross-section of the imidazole group compared with the piperazine ring of Hoechst 33258 and therefore a smaller perturbation in groove width. The higher binding affinity to DNA shown by this analogue compared with Hoechst 33258 itself, has been rationalised in terms of these differences.

Base Sequence↗
PubMed1995

Sequence-dependent drug binding to the minor groove of DNA: crystal structure of the DNA dodecamer d(CGCAAATTTGCG)2 complexed with propamidine.

The DNA-binding ligand propamidine, an analogue of the drug pentamidine which is used in the treatment of acquired immune deficiency syndrome (AIDS)-associated Pneumocystis carinii, has been cocrystallized with the DNA sequence d(CGCAAATTTGCG)2, and the crystal structure of the complex has been determined using data from 8 to 2.2 A resolution. The R factor converged to 15.5% with the inclusion of 73 water molecules. The structure shows binding of the propamidine molecule within the AT tract of the DNA minor groove with a shift from the center of the duplex toward the 3' end of ca. 2 A. The long AT tract of six base pairs in length allows the propamidine many potential binding sites in the DNA groove, and its binding is seen to occur where there is least perturbation to the DNA from that seen in the native structure. The interactions with bases are distinct from those previously observed for the sequence d(CGCGAATTCGCG)2.

Antifungal Agents↗