Samar Hasnain | University of Liverpool (original) (raw)

Papers by Samar Hasnain

Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 1986

... [4] SS Hasnain, GP Diakun and PD Quinn, unpublished work. [5] MJ van der Hoek, W. Werner and ... more ... [4] SS Hasnain, GP Diakun and PD Quinn, unpublished work. [5] MJ van der Hoek, W. Werner and P. van Zuylen, these Proceedings (Synchrotron Radiation Instrumentation, Stanford, 1985) Nucl. Instr. and Meth. A246 (1986) 190. [6] J. Bijleveld, SS Hasnain, AP Kaan, G. Luijckx ...

Acta Crystallographica Section A Foundations and Advances, 2018

Springer Proceedings in Physics, 1984

The copper containing enzymes superoxide dismutase, dopamine monooxygenase and plasma amine oxida... more The copper containing enzymes superoxide dismutase, dopamine monooxygenase and plasma amine oxidase while functionally diverse are often classified together as ‘non-blue’ or ‘type 2’ on the basis of the similarity of their optical and EPR spectroscopic properties to those of simple mononuclear complexes[1]. X-ray absorption spectroscopy offers a further method of examining the structural relationships within this class of copper proteins. In this paper we summarise the results of EXAFS studies, which provide evidence of structural homologies and have identified imidazole coordination in all three enzyme systems. In the case of native superoxide dismutase where a crystal structure is available to 2A resolution[2, 3], comparison of EXAFS and crystal lographic coordinates using molecular graphics has provided extra insights into the local structure of the active site.

Acta Crystallographica Section A Foundations and Advances, 2021

iScience, May 15, 2020

Mislocalization, cleavage, and aggregation of the human protein TDP-43 is found in many neurodege... more Mislocalization, cleavage, and aggregation of the human protein TDP-43 is found in many neurodegenerative diseases. As is the case with many other proteins that are completely or partially structurally disordered, production of full-length recombinant TDP-43 in the quantities necessary for structural characterization has proved difficult. We show that the full-length TDP-43 protein and two truncated N-terminal constructs 1-270 and 1-263 can be heterologously expressed in E. coli. Full-length TDP-43 could be prevented from aggregation during purification using a detergent. Crystals grown from an N-terminal construct (1-270) revealed only the N-terminal domain (residues 1-80) with molecules arranged as parallel spirals with neighboring molecules arranged in head-to-tail fashion. To obtain detergent-free, full-length TDP-43 we mutated all six tryptophan residues to alanine. This provided sufficient soluble protein to collect small-angle X-ray scattering data. Refining relative position...

All in-text references underlined in blue are linked to publications on ResearchGate, letting you... more All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately.

Acta Crystallographica Section D Structural Biology, 2020

Methionine adenosyltransferase (MAT) deficiency, characterized by isolated persistent hypermethio... more Methionine adenosyltransferase (MAT) deficiency, characterized by isolated persistent hypermethioninemia (IPH), is caused by mutations in the MAT1A gene encoding MATαl, one of the major hepatic enzymes. Most of the associated hypermethioninemic conditions are inherited as autosomal recessive traits; however, dominant inheritance of hypermethioninemia is caused by an Arg264His (R264H) mutation. This mutation has been confirmed in a screening programme of newborns as the most common mutation in babies with IPH. Arg264 makes an inter-subunit salt bridge located at the dimer interface where the active site assembles. Here, it is demonstrated that the R264H mutation results in greatly reduced MAT activity, while retaining its ability to dimerize, indicating that the lower activity arises from alteration at the active site. The first crystallographic structure of the apo form of the wild-type MATαl enzyme is provided, which shows a tetrameric assembly in which two compact dimers combine t...

Biological Nitrogen Fixation for the 21st Century, 1998

Nature Communications, 2021

The SARS-CoV-2 pandemic has triggered global efforts to develop therapeutics. The main protease o... more The SARS-CoV-2 pandemic has triggered global efforts to develop therapeutics. The main protease of SARS-CoV-2 (Mpro), critical for viral replication, is a key target for therapeutic development. An organoselenium drug called ebselen has been demonstrated to have potent Mpro inhibition and antiviral activity. We have examined the binding modes of ebselen and its derivative in Mpro via high resolution co-crystallography and investigated their chemical reactivity via mass spectrometry. Stronger Mpro inhibition than ebselen and potent ability to rescue infected cells were observed for a number of derivatives. A free selenium atom bound with cysteine of catalytic dyad has been revealed in crystallographic structures of Mpro with ebselen and MR6-31-2 suggesting hydrolysis of the enzyme bound organoselenium covalent adduct and formation of a phenolic by-product, confirmed by mass spectrometry. The target engagement with selenation mechanism of inhibition suggests wider therapeutic applicat...

Chemical Science, 2020

Observation of side-on copper-nitrosyl intermediate and its confirmation by DFT during catalysis ... more Observation of side-on copper-nitrosyl intermediate and its confirmation by DFT during catalysis of copper nitrite reductases.

Glass Science and Technology, 1990

IUCrJ, 2020

Copper-containing nitrite reductases (CuNiRs) are found in all three kingdoms of life and play a ... more Copper-containing nitrite reductases (CuNiRs) are found in all three kingdoms of life and play a major role in the denitrification branch of the global nitrogen cycle where nitrate is used in place of dioxygen as an electron acceptor in respiratory energy metabolism. Several C- and N-terminal redox domain tethered CuNiRs have been identified and structurally characterized during the last decade. Our understanding of the role of tethered domains in these new classes of three-domain CuNiRs, where an extra cytochrome or cupredoxin domain is tethered to the catalytic two-domain CuNiRs, has remained limited. This is further compounded by a complete lack of substrate-bound structures for these tethered CuNiRs. There is still no substrate-bound structure for any of the as-isolated wild-type tethered enzymes. Here, structures of nitrite and product-bound states from a nitrite-soaked crystal of the N-terminal cupredoxin-tethered enzyme from the Hyphomicrobium denitrificans strain 1NES1 (Hd 1...

Journal of Synchrotron Radiation, 2018

Synchrotron Radiation is well established as an important publication of the IUCr, but we had a '... more Synchrotron Radiation is well established as an important publication of the IUCr, but we had a 'fun journey' getting there. During the launch period and subsequent years, Dr Kamitsubo made a huge contribution to the journal, helping to secure its viability. He

Communications Biology, 2020

Mutations to the gene encoding superoxide dismutase-1 (SOD1) were the first genetic elements disc... more Mutations to the gene encoding superoxide dismutase-1 (SOD1) were the first genetic elements discovered that cause motor neuron disease (MND). These mutations result in compromised SOD1 dimer stability, with one of the severest and most common mutations Ala4Val (A4V) displaying a propensity to monomerise and aggregate leading to neuronal death. We show that the clinically used ebselen and related analogues promote thermal stability of A4V SOD1 when binding to Cys111 only. We have developed a A4V SOD1 differential scanning fluorescence-based assay on a C6S mutation background that is effective in assessing suitability of compounds. Crystallographic data show that the selenium atom of these compounds binds covalently to A4V SOD1 at Cys111 at the dimer interface, resulting in stabilisation. This together with chemical amenability for hit expansion of ebselen and its on-target SOD1 pharmacological chaperone activity holds remarkable promise for structure-based therapeutics for MND using...

Neisseria meningitidis is carried by nearly a billion humans, causing developmental impairment an... more Neisseria meningitidis is carried by nearly a billion humans, causing developmental impairment and over 100 000 deaths a year. A quinol-dependent nitric oxide reductase (qNOR) plays a critical role in the survival of the bacterium in the human host. X-ray crystallographic analyses of qNOR, including that from N. meningitidis (NmqNOR) reported here at 3.15 Å resolution, show monomeric assemblies, despite the more active dimeric sample being used for crystallization. Cryo-electron microscopic analysis of the same chromatographic fraction of NmqNOR, however, revealed a dimeric assembly at 3.06 Å resolution. It is shown that zinc (which is used in crystallization) binding near the dimer-stabilizing TMII region contributes to the disruption of the dimer. A similar destabilization is observed in the monomeric ($85 kDa) cryo-EM structure of a mutant (Glu494Ala) qNOR from the opportunistic pathogen Alcaligenes (Achromobacter) xylosoxidans, which primarily migrates as a monomer. The monomer-dimer transition of qNORs seen in the cryo-EM and crystallographic structures has wider implications for structural studies of multimeric membrane proteins. X-ray crystallographic and cryo-EM structural analyses have been performed on the same chromatographic fraction of NmqNOR to high resolution. This represents one of the first examples in which the two approaches have been used to reveal a monomeric assembly in crystallo and a dimeric assembly in vitrified cryo-EM grids. A number of factors have been identified that may trigger the destabilization of helices that are necessary to preserve the integrity of the dimer. These include zinc binding near the entry of the putative proton-transfer channel and the preservation of the conformational integrity of the active site. The mutation near the active site results in disruption of the active site, causing an additional destabilization of helices (TMIX and TMX) that flank the proton-transfer channel helices, creating an inert monomeric enzyme. research papers IUCrJ (2020). 7, 404-415 M. Arif M. Jamali et al. Quinol-dependent nitric oxide reductase 405

Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences, 2019

The development of synchrotron science over the last 50 years is reviewed from the perspective of... more The development of synchrotron science over the last 50 years is reviewed from the perspective of the authors' own scientific programmes. This article is part of the theme issue ‘Fifty years of synchrotron science: achievements and opportunities’.

Acta Crystallographica Section D Structural Biology, 2019

Solute carriers are a large class of transporters that play key roles in normal and disease physi... more Solute carriers are a large class of transporters that play key roles in normal and disease physiology. Among the solute carriers, heteromeric amino-acid transporters (HATs) are unique in their quaternary structure. LAT1–CD98hc, a HAT, transports essential amino acids and drugs across the blood–brain barrier and into cancer cells. It is therefore an important target both biologically and therapeutically. During the course of this work, cryo-EM structures of LAT1–CD98hc in the inward-facing conformation and in either the substrate-bound or apo states were reported to 3.3–3.5 Å resolution [Yan et al. (2019), Nature (London), 568, 127–130]. Here, these structures are analyzed together with our lower resolution cryo-EM structure, and multibody 3D auto-refinement against single-particle cryo-EM data was used to characterize the dynamics of the interaction of CD98hc and LAT1. It is shown that the CD98hc ectodomain and the LAT1 extracellular surface share no substantial interface. This all...