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1.  IMPROVED SYNTHESIS OF 10-(2-ALKYLAMINO-2-OXOETHYL)-1,4,7,10-TETRAAZACYCLODODECANE-1,4,7-TRIACETIC ACID DERIVATIVES BEARING ACID-SENSITIVE LINKERS 
Synthetic communications  2013;44(3):10.1080/00397911.2013.813547.
Alkylation of the hydrobromide salts of 1,4,7-tris(methoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane and 1,4,7-tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane with appropriate α-bromoacetamides, followed by hydrolysis, provides convenient access to 10-(2-alkylamino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid derivatives that contain acid-sensitive functional groups. The utility of the method is demonstrated by improved syntheses of two known DOTA monoamides bearing acid-sensitive ω-tritylthio alkyl chains in much higher yields based on cyclen as the starting material.
doi:10.1080/00397911.2013.813547
PMCID: PMC3866964  PMID: 24363464
Cyclen; DOTA monoamide; DO3A monoamide; medical imaging; synthesis
2.  Molecular Model of a Soluble Guanylyl Cyclase Fragment Determined by Small-Angle X–ray Scattering and Chemical Cross-Linking 
Biochemistry  2013;52(9):1568-1582.
Soluble guanylyl/guanylate cyclase (sGC) converts GTP to cGMP after binding nitric oxide, leading to smooth muscle relaxation and vasodilation. Impaired sGC activity is common in cardiovascular disease and sGC stimulatory compounds are greatly sought. sGC is a 150 kDa heterodimeric protein with two H-NOX domains (one with heme, one without), two PAS domains, a coiled-coil domain and two cyclase domains. Binding of NO to the sGC heme leads to proximal histidine release and stimulation of catalytic activity. To begin understanding how binding leads to activation, we examined truncated sGC proteins from Manduca sexta (tobacco hornworm) that bind NO, CO and stimulatory compound YC-1, but lack the cyclase domains. We determined the overall shape of truncated Ms sGC using analytical ultracentrifugation and small angle X-ray scattering (SAXS), revealing an elongated molecule 115 Å by 90 Å by 75 Å. Binding of NO, CO or YC-1 had little effect on shape. Using chemical cross-linking and tandem mass spectrometry, we identified 20 intermolecular contacts, allowing us to fit homology models of the individual domains into the SAXS-derived molecular envelope. The resulting model displays a central parallel coiled-coil platform upon which the H-NOX and PAS domains are assembled. The β1 H-NOX and α1 PAS domains are in contact and form the core signaling complex, while the α1 H-NOX domain can be removed without significant effect on ligand binding or overall shape. Removal of 21 residues from the C-terminus yields a protein with dramatically increased proximal histidine release rates upon NO binding.
doi:10.1021/bi301570m
PMCID: PMC3607398  PMID: 23363317
3.  3-(4-Bromo­phen­yl)-1-butyl-5-[1-(2-chloro-6-methyl­phen­yl)-1H-tetra­zol-5-yl]imidazolidine-2,4-dione 
In the title mol­ecule, C21H20BrClN6O2, the chloro-substituted benzene ring forms a dihedral angle of 77.84 (7)° with the tetra­zole ring and the bromo-substituted ring forms a dihedral angle of 43.95 (6)° with the imidazole ring. The dihedral angle between the tetra­zole and imidazole rings is 67.42 (8)°. The terminal methyl group of the butyl substituent is disordered over two sets of sites, with refined occupancies 0.67 (3) and 0.33 (3). In the crystal, there is a short Br⋯N contact of 3.183 (2) Å.
doi:10.1107/S1600536813016000
PMCID: PMC3770378  PMID: 24046663
4.  (Z)-N-tert-Butyl-2-(4-meth­oxy­anilino)-N′-(4-meth­oxy­phen­yl)-2-phenyl­acetimidamide 
In the crystal of the title compound, C26H31N3O2, pairs of N—H⋯O hydrogen bonds link molecules, forming inversion dimers, which enclose an R 2 2(20) ring motif. One N atom does not form hydrogen bonds and lies in a hydro­phobic pocket with closest inter­molecular contacts of 4.196 (2) and 4.262 (2) Å.
doi:10.1107/S1600536813012877
PMCID: PMC3685058  PMID: 23795077
5.  tert-Butyl 4-(3,4-dichloro­anilino)piperidine-1-carboxyl­ate 
In the title compound, C16H22Cl2N2O2, the substituted piperidine ring adopts a chair conformation with both substituents in equatorial positions. In the crystal, N—H⋯O and C—H⋯O hydrogen bonds connect mol­ecules into ribbons along the a-axis direction.
doi:10.1107/S1600536812051896
PMCID: PMC3569265  PMID: 23424488
6.  Conformations of the apo-, substrate-bound and phosphate-bound ATP-binding domain of the Cu(II) ATPase CopB illustrate coupling of domain movement to the catalytic cycle 
Bioscience Reports  2012;32(Pt 5):443-453.
Heavy metal P1B-type ATPases play a critical role in cell survival by maintaining appropriate intracellular metal concentrations. Archaeoglobus fulgidus CopB is a member of this family that transports Cu(II) from the cytoplasm to the exterior of the cell using ATP as energy source. CopB has a 264 amino acid ATPBD (ATP-binding domain) that is essential for ATP binding and hydrolysis as well as ultimately transducing the energy to the transmembrane metal-binding site for metal occlusion and export. The relevant conformations of this domain during the different steps of the catalytic cycle are still under discussion. Through crystal structures of the apo- and phosphate-bound ATPBDs, with limited proteolysis and fluorescence studies of the apo- and substrate-bound states, we show that the isolated ATPBD of CopB cycles from an open conformation in the apo-state to a closed conformation in the substrate-bound state, then returns to an open conformation suitable for product release. The present work is the first structural report of an ATPBD with its physiologically relevant product (phosphate) bound. The solution studies we have performed help resolve questions on the potential influence of crystal packing on domain conformation. These results explain how phosphate is co-ordinated in ATPase transporters and give an insight into the physiologically relevant conformation of the ATPBD at different steps of the catalytic cycle.
doi:10.1042/BSR20120048
PMCID: PMC3475447  PMID: 22663904
ATPase transporter; ATP-binding domain (ATPBD); CopB; copper; crystal structure; metal transport.; A-domain, actuator domain; AMPPCP, adenosine 5′-(β,γ-methylene)triphosphate; ATPBD, ATP-binding domain; HAD, haloacid dehalogenase; IPTG, isopropyl β-D-thiogalactoside; Lp-CopA, Legionella pneumophila CopA; MBD, metal-binding domain; N-domain, nucleotide-binding domain; p[NH]ppA, adenosine 5′-[β,γ-imido]triphosphate; PEG, poly(ethylene glycol); P-domain, phosphorylation doamin; RMSD, root mean square deviation; SERCA1, sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 1; SSRL, Stanford Synchrotron Radiation Lightsource
7.  The development of one-stop wide-awake dupuytren's fasciectomy service: a retrospective review 
JRSM Short Reports  2012;3(7):48.
Objectives
To detail the transition to a totally one-stop wide-awake (OSWA) Dupuytren's contracture surgical service.
Design
Retrospective review of Dupuytren's component of last 1000 OSWA cases.
Setting
The UK's first totally one-stop wide-awake orthopaedic service.
Participants
270 patients with Dupuytren's contracture out of the last 1000 OSWA cases.
Main outcome measures
Surgical outcomes, patient satisfaction and cost-effectiveness and efficiency.
Results
The OSWA Dupuytren's model is safe, efficient and effective; with a low complication rate, extremely high patient satisfaction; and cost-savings to the nhs of £2500 per case treated. The service saved the NHS approximately £675,000 for the 270 cases presented.
Conclusions
A totally one-stop wide-awake Dupuytren's Contracture service is practicable and feasible alternative to the conventional treatment pathway, with benefits in terms of efficiency and cost-effectiveness.
doi:10.1258/shorts.2012.012050
PMCID: PMC3422854  PMID: 22908029
8.  2,4-Diphenyl-6-trifluoro­methyl-2,3-dihydro-1H,5H-pyrrolo­[3,4-c]pyrrole-1,3-dione 
The asymmetric unit of the title compound, C19H11F3N2O2, contains two crystallographically unique mol­ecules which differ in the rotation of a phenyl ring and a –CF3 substituent. The dihedral angles involving the pyrrole ring and the attached phenyl ring are 62.82 (8) and 71.54 (7)° in the two molecules. The difference in the rotation of the CF3 groups with respect to the pyrrolo rings to which they are attached is 23.5(1)°. For one mol­ecule, there is a close contact between an H atom and the centroid of the phenyl ring of an adjacent mol­ecule (2.572 Å). A similar contact is lacking in the second mol­ecule. In the crystal, N—H⋯O inter­actions connect adjacent mol­ecules into a chain normal to (01). Crystallographically unique mol­ecules alternate along the hydrogen-bonded chains.
doi:10.1107/S1600536812001675
PMCID: PMC3275242  PMID: 22347098
9.  Structure of a 6-pyruvoyltetrahydropterin synthase homolog from Streptomyces coelicolor 
The X-ray crystal structure of the 6-pyruvoyltetrahydropterin synthase (PTPS) homolog from Streptomyces coelicolor, SCO 6650, was solved at 1.5 Å resolution. SCO 6650 forms a hexameric T-fold that closely resembles other PTPS proteins. The biological activity of SCO 6650 is unknown, but it lacks both a required active-site zinc metal ion and the essential catalytic triad and does not catalyze the PTPS reaction. However, SCO 6650 maintains active-site residues consistent with binding a pterin-like substrate.
doi:10.1107/S1744309108027048
PMCID: PMC2564891  PMID: 18931427
10.  Structure of a 6-pyruvoyltetrahydropterin synthase homolog from Streptomyces coelicolor  
The X-ray crystal structure of a 6-pyruvoyltetrahydropterin synthase homolog of unknown function has been determined at 1.5 Å resolution. The protein retains residues required for pterin binding, but nearly all catalytic residues are missing.
The X-ray crystal structure of the 6-pyruvoyltetrahydropterin synthase (PTPS) homolog from Streptomyces coelicolor, SCO 6650, was solved at 1.5 Å resolution. SCO 6650 forms a hexameric T-fold that closely resembles other PTPS proteins. The biological activity of SCO 6650 is unknown, but it lacks both a required active-site zinc metal ion and the essential catalytic triad and does not catalyze the PTPS reaction. However, SCO 6650 maintains active-site residues consistent with binding a pterin-like substrate.
doi:10.1107/S1744309108027048
PMCID: PMC2564891  PMID: 18931427
SCO 6650; Streptomyces coelicolor; 6-pyruvoyltetrahydropterin synthase homolog
11.  Structure of the Y94F mutant of Escherichia coli thymidylate synthase 
Mutation of Tyr94 of E. coli thymidylate synthase to phenylalanine leads to a protein with k cat reduced by a factor of 400. The Y94F structure is essentially identical to the wild-type structure, which is consistent with a catalytic role for the phenolic OH.
Tyr94 of Escherichia coli thymidylate synthase is thought to be involved, either directly or by activation of a water molecule, in the abstraction of a proton from C5 of the 2′-deoxyuridine 5′-monophosphate (dUMP) substrate. Mutation of Tyr94 leads to a 400-fold loss in catalytic activity. The structure of the Y94F mutant has been determined in the native state and as a ternary complex with thymidine 5′-monophosphate (dTMP) and 10-propargyl 5,8-dideazafolate (PDDF). There are no structural changes ascribable to the mutation other than loss of a water molecule hydrogen bonded to the tyrosine OH, which is consistent with a catalytic role for the phenolic OH.
doi:10.1107/S1744309106029691
PMCID: PMC2242863  PMID: 16946460
tyrosine mutant; TLS; catalytic mechanism

Results 1-11 (11)