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  1. Article ; Online: Do maternal haemodynamics have a causal influence on treatment for gestational diabetes?

    Anness, Abigail R / Foster, Michael / Osman, Mohammed W / Webb, David / Robinson, Thompson / Khalil, Asma / Walkinshaw, Neil / Mousa, Hatem A

    Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology

    2024  Volume 44, Issue 1, Page(s) 2307883

    Abstract: Background: Arterial stiffening is believed to contribute to the worsening of insulin resistance, and factors which are associated with needing pharmacological treatment of gestational diabetes (GDM), such as maternal obesity or advanced age, are ... ...

    Abstract Background: Arterial stiffening is believed to contribute to the worsening of insulin resistance, and factors which are associated with needing pharmacological treatment of gestational diabetes (GDM), such as maternal obesity or advanced age, are associated with impaired cardiovascular adaptation to pregnancy. In this observational study, we aimed to investigate causal relationships between maternal haemodynamics and treatment requirement amongst women with GDM.
    Methods: We assessed maternal haemodynamics in women with GDM, comparing those who remained on dietary treatment with those who required pharmacological management. Maternal haemodynamics were assessed using the Arteriograph® (TensioMed Ltd, Budapest, Hungary) and the NICOM® non-invasive bio-reactance method (Cheetah Medical, Portland, Oregon, USA). A graphical causal inference technique was used for statistical analysis.
    Results: 120 women with GDM were included in the analysis. Maternal booking BMI was identified as having a causative influence on treatment requirement, with each unit increase in BMI increasing the odds of needing metformin and/or insulin therapy by 12% [OR 1.12 (1.02 - 1.22)]. The raw values of maternal heart rate (87.6 ± 11.7 vs. 92.9 ± 11.90 bpm,
    Conclusions: Maternal BMI at booking has a causal, rather than simply associational, relationship on the need for pharmacological treatment of GDM. No significant causal relationships were found between maternal haemodynamics and the need for pharmacological treatment.
    MeSH term(s) Pregnancy ; Female ; Humans ; Diabetes, Gestational/drug therapy ; Metformin/therapeutic use ; Hemodynamics ; Risk Factors ; Insulin/therapeutic use
    Chemical Substances Metformin (9100L32L2N) ; Insulin
    Language English
    Publishing date 2024-02-22
    Publishing country England
    Document type Observational Study ; Journal Article
    ZDB-ID 604639-3
    ISSN 1364-6893 ; 0144-3615
    ISSN (online) 1364-6893
    ISSN 0144-3615
    DOI 10.1080/01443615.2024.2307883
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  2. Article ; Online: The unusual kinetics of lactate dehydrogenase of Schistosoma mansoni and their role in the rapid metabolic switch after penetration of the mammalian host.

    Bexkens, Michiel L / Martin, Olivier M F / van den Heuvel, Jos M / Schmitz, Marion G J / Teusink, Bas / Bakker, Barbara M / van Hellemond, Jaap J / Haanstra, Jurgen R / Walkinshaw, Malcolm D / Tielens, Aloysius G M

    International journal for parasitology

    2024  

    Abstract: Lactate dehydrogenase (LDH) from Schistosoma mansoni has peculiar properties for a eukaryotic LDH. Schistosomal LDH (SmLDH) isolated from schistosomes, and the recombinantly expressed protein, are strongly inhibited by ATP, which is neutralized by ... ...

    Abstract Lactate dehydrogenase (LDH) from Schistosoma mansoni has peculiar properties for a eukaryotic LDH. Schistosomal LDH (SmLDH) isolated from schistosomes, and the recombinantly expressed protein, are strongly inhibited by ATP, which is neutralized by fructose-1,6-bisphosphate (FBP). In the conserved FBP/anion binding site we identified two residues in SmLDH (Val187 and Tyr190) that differ from the conserved residues in LDHs of other eukaryotes, but are identical to conserved residues in FBP-sensitive prokaryotic LDHs. Three-dimensional (3D) models were generated to compare the structure of SmLDH with other LDHs. These models indicated that residues Val187, and especially Tyr190, play a crucial role in the interaction of FBP with the anion pocket of SmLDH. These 3D models of SmLDH are also consistent with a competitive model of SmLDH inhibition in which ATP (inhibitor) and FBP (activator) compete for binding in a well-defined anion pocket. The model of bound ATP predicts a distortion of the nearby key catalytic residue His195, resulting in enzyme inhibition. To investigate a possible physiological role of this allosteric regulation of LDH in schistosomes we made a kinetic model in which the allosteric regulation of the glycolytic enzymes can be varied. The model showed that inhibition of LDH by ATP prevents fermentation to lactate in the free-living stages in water and ensures complete oxidation via the Krebs cycle of the endogenous glycogen reserves. This mechanism of allosteric inhibition by ATP prevents the untimely depletion of these glycogen reserves, the only fuel of the free-living cercariae. Neutralization by FBP of this ATP inhibition of LDH prevents accumulation of glycolytic intermediates when S. mansoni schistosomula are confronted with the sudden large increase in glucose availability upon penetration of the final host. It appears that the LDH of S. mansoni is special and well suited to deal with the variations in glucose availability the parasite encounters during its life cycle.
    Language English
    Publishing date 2024-03-15
    Publishing country England
    Document type Journal Article
    ZDB-ID 120518-3
    ISSN 1879-0135 ; 0020-7519
    ISSN (online) 1879-0135
    ISSN 0020-7519
    DOI 10.1016/j.ijpara.2024.03.005
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  3. Article ; Online: A Strep A vaccine global demand and return on investment forecast to inform industry research and development prioritization.

    Walkinshaw, Donald R / Wright, Meghan E E / Williams, Marni / Scarapicchia, Tanya M F / Excler, Jean-Louis / Wiley, Ryan E / Mullin, Anne E

    NPJ vaccines

    2023  Volume 8, Issue 1, Page(s) 113

    Abstract: Investment in Strep A vaccine R&D is disproportionately low relative to the large burden of Strep ...

    Abstract Investment in Strep A vaccine R&D is disproportionately low relative to the large burden of Strep A diseases globally. This study presents a novel Strep A vaccine global demand and financial forecast model with estimates of potential global demand and associated revenue and profits for a hypothetical Strep A vaccine as well as a net present value (NPV) analysis of return on capital investments required to develop the vaccine. A positive NPV was calculated for a variety of developer scenarios and target populations, including the global rollout of the vaccine in private and public markets by a multinational pharmaceutical corporation and a staged rollout by a developing country vaccine manufacturer for both infant and child populations. The results suggest there is a viable commercial market for a Strep A vaccine. It is hoped that this study will help to inform industry decision-making and drive increased prioritization of, and investment in, Strep A vaccine research and development.
    Language English
    Publishing date 2023-08-09
    Publishing country England
    Document type Journal Article
    ISSN 2059-0105
    ISSN (online) 2059-0105
    DOI 10.1038/s41541-023-00690-2
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  4. Article ; Online: Consensus docking: improving the reliability of docking in a virtual screening context.

    Houston, Douglas R / Walkinshaw, Malcolm D

    Journal of chemical information and modeling

    2013  Volume 53, Issue 2, Page(s) 384–390

    Abstract: Structure-based virtual screening relies on scoring the predicted binding modes of compounds docked into the target. Because the accuracy of this scoring relies on the accuracy of the docking, methods that increase docking accuracy are valuable. Here, we ...

    Abstract Structure-based virtual screening relies on scoring the predicted binding modes of compounds docked into the target. Because the accuracy of this scoring relies on the accuracy of the docking, methods that increase docking accuracy are valuable. Here, we present a relatively straightforward method for improving the probability of identifying accurately docked poses. The method is similar in concept to consensus scoring schemes, which have been shown to increase ranking power and thus hit rates, but combines information about predicted binding modes rather than predicted binding affinities. The pose prediction success rate of each docking program alone was found in this trial to be 55% for Autodock, 58% for DOCK, and 64% for Vina. By using more than one docking program to predict the binding pose, correct poses were identified in 82% or more of cases, a significant improvement. In a virtual screen, these more reliably posed compounds can be preferentially advanced to subsequent scoring stages to improve hit rates. Consensus docking can be easily introduced into established structure-based virtual screening methodologies.
    MeSH term(s) Bacteroides/enzymology ; Databases, Protein ; Drug Design ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Hepacivirus/enzymology ; Ligands ; Molecular Docking Simulation/methods ; Probability ; Protein Binding ; RNA-Dependent RNA Polymerase/antagonists & inhibitors ; RNA-Dependent RNA Polymerase/metabolism ; Software ; beta-N-Acetylhexosaminidases/antagonists & inhibitors ; beta-N-Acetylhexosaminidases/metabolism
    Chemical Substances Enzyme Inhibitors ; Ligands ; RNA-Dependent RNA Polymerase (EC 2.7.7.48) ; hexosaminidase C (EC 3.2.1.50) ; beta-N-Acetylhexosaminidases (EC 3.2.1.52)
    Language English
    Publishing date 2013-02-07
    Publishing country United States
    Document type Journal Article
    ZDB-ID 190019-5
    ISSN 1549-960X ; 0095-2338
    ISSN (online) 1549-960X
    ISSN 0095-2338
    DOI 10.1021/ci300399w
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    Zs.A 1230: Show issues Location:
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  5. Article ; Online: Maternal hemodynamics and neonatal birth weight in pregnancies complicated by gestational diabetes: new insights from novel causal inference analysis modeling.

    Anness, A R / Clark, A / Melhuish, K / Leone, F M T / Osman, M W / Webb, D / Robinson, T / Walkinshaw, N / Khalil, A / Mousa, H A

    Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology

    2022  Volume 60, Issue 2, Page(s) 215–222

    Abstract: Objective: Normal pregnancy is characterized by significant changes in maternal hemodynamics that are associated with fetal growth. Pregnancies complicated by gestational diabetes mellitus (GDM) are associated with large-for-gestational age and ... ...

    Abstract Objective: Normal pregnancy is characterized by significant changes in maternal hemodynamics that are associated with fetal growth. Pregnancies complicated by gestational diabetes mellitus (GDM) are associated with large-for-gestational age and macrosomia, but the relationship between maternal hemodynamic parameters and birth weight (BW) among women with GDM has not been established. Our objective was to investigate the influence of maternal hemodynamics on neonatal BW in healthy pregnancies and in those complicated by GDM.
    Methods: This was a prospective, cross-sectional case-control study of women aged ≥ 16 years with a singleton viable pregnancy, recruited between January 2016 and February 2021 at Leicester Royal Infirmary, Leicester, UK. GDM was defined as a fasting glucose level ≥ 5.3 mmol/L and/or serum glucose level ≥ 7.8 mmol/L, 2 h following a 75-g oral glucose load. We collected data on maternal characteristics and pregnancy outcome, including body mass index (BMI) at booking and BW centile adjusted for gestational age at delivery. Maternal hemodynamic parameters were assessed at 34-42 weeks' gestation using the Arteriograph® and bioreactance techniques. Graphical causal inference methodology was used to identify causal effects of the measured variables on neonatal BW centile.
    Results: Included in the analysis were 141 women with GDM and 136 normotensive non-diabetic pregnant controls. 62% of the women with GDM were managed pharmacologically, with metformin and/or insulin. Variables included in the final model were cardiac output (CO), mean arterial pressure (MAP), total peripheral resistance (TPR), aortic augmentation index (AIx), aortic pulse wave velocity (PWV) and BMI at booking. Among the controls, maternal BMI, CO and aortic PWV were significantly associated with neonatal BW. Each SD increase in booking BMI produced an increase of 8.4 BW centiles (P = 0.002), in CO produced an increase of 9.4 BW centiles (P = 0.008) and in aortic PWV produced an increase of 7.1 BW centiles (P = 0.017). We found no significant relationship between MAP, TPR or aortic AIx and neonatal BW. Maternal hemodynamics influenced neonatal BW among the women with GDM in a similar manner to that in the control group, but only the relationship between maternal BMI and neonatal BW reached statistical significance, with a 1-SD increase in BMI producing an increase of 6.1 BW centiles (P = 0.019).
    Conclusions: Maternal BMI, CO and PWV were determinants of BW in our control group. The relationship between maternal hemodynamics and neonatal BW was similar between women with GDM and healthy controls. Our findings therefore suggest that fetal growth restriction in pregnancies complicated by GDM may indicate maternal cardiovascular dysfunction. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
    MeSH term(s) Birth Weight ; Case-Control Studies ; Cross-Sectional Studies ; Diabetes, Gestational ; Female ; Glucose ; Hemodynamics ; Humans ; Infant, Newborn ; Pregnancy ; Pregnancy Outcome ; Prospective Studies ; Pulse Wave Analysis
    Chemical Substances Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2022-02-09
    Publishing country England
    Document type Journal Article
    ZDB-ID 1073183-0
    ISSN 1469-0705 ; 0960-7692
    ISSN (online) 1469-0705
    ISSN 0960-7692
    DOI 10.1002/uog.24864
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    Zs.A 3214: Show issues Location:
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  6. Article ; Online: Structure- and ligand-based virtual screening identifies new scaffolds for inhibitors of the oncoprotein MDM2.

    Houston, Douglas R / Yen, Li-Hsuan / Pettit, Simon / Walkinshaw, Malcolm D

    PloS one

    2015  Volume 10, Issue 4, Page(s) e0121424

    Abstract: A major challenge in the field of ligand discovery is to identify chemically useful fragments that can be developed into inhibitors of specific protein-protein interactions. Low molecular weight fragments (with molecular weight less than 250 Da) are ... ...

    Abstract A major challenge in the field of ligand discovery is to identify chemically useful fragments that can be developed into inhibitors of specific protein-protein interactions. Low molecular weight fragments (with molecular weight less than 250 Da) are likely to bind weakly to a protein's surface. Here we use a new virtual screening procedure which uses a combination of similarity searching and docking to identify chemically tractable scaffolds that bind to the p53-interaction site of MDM2. The binding has been verified using capillary electrophoresis which has proven to be an excellent screening method for such small, weakly binding ligands.
    MeSH term(s) Binding Sites ; Electrophoresis, Capillary ; Fluorescence Polarization ; Humans ; Imidazoles/chemistry ; Imidazoles/metabolism ; Ligands ; Molecular Docking Simulation ; Piperazines/chemistry ; Piperazines/metabolism ; Protein Binding ; Protein Interaction Domains and Motifs ; Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors ; Proto-Oncogene Proteins c-mdm2/metabolism ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/metabolism
    Chemical Substances Imidazoles ; Ligands ; Piperazines ; Small Molecule Libraries ; nutlin 3 (53IA0V845C) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27)
    Language English
    Publishing date 2015-04-17
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0121424
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  7. Article: Histone deacetylase inhibitors as novel anticancer therapeutics.

    Walkinshaw, D R / Yang, X J

    Current oncology (Toronto, Ont.)

    2008  Volume 15, Issue 5, Page(s) 237–243

    Abstract: Histone deacetylase inhibitors represent a promising new class of compounds for the treatment of cancer. Inhibitors of this kind currently under clinical evaluation mainly target the classical (Rpd3/Hda1) family of histone deacetylases. Of particular ... ...

    Abstract Histone deacetylase inhibitors represent a promising new class of compounds for the treatment of cancer. Inhibitors of this kind currently under clinical evaluation mainly target the classical (Rpd3/Hda1) family of histone deacetylases. Of particular note, the U.S. Food and Drug Administration recently approved the first histone deacetylase inhibitor (Zolinza: Merck and Co., Whitehouse Station, NJ, U.S.A.) for the treatment of cutaneous T-cell lymphoma. Dozens of such inhibitors are now in phase ii-iii clinical trials, sometimes in combination with other chemotherapy drugs, for diverse cancer types, including both hematologic and solid tumours. In this mini-review, we provide an overview of the histone deacetylase superfamily, highlight the positive results of deacetylase inhibitors in cancer clinical trials, and comment on the prospects for the next generation of such inhibitors.
    Language English
    Publishing date 2008-10-22
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1236972-x
    ISSN 1718-7729 ; 1198-0052
    ISSN (online) 1718-7729
    ISSN 1198-0052
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    Zs.A 4305: Show issues Location:
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  8. Article ; Online: A Molecular Dynamics Study of Allosteric Transitions in Leishmania mexicana Pyruvate Kinase.

    Naithani, Ankita / Taylor, Paul / Erman, Burak / Walkinshaw, Malcolm D

    Biophysical journal

    2015  Volume 109, Issue 6, Page(s) 1149–1156

    Abstract: ... active-site α6' helix, which would adopt a helical conformation in the active R-state and a less structured ... to R transition. The transitions predicted by these simulations are largely consistent with the Monod ...

    Abstract A comparative molecular dynamics analysis of the pyruvate kinase from Leishmania mexicana is presented in the absence and presence of the allosteric effector fructose 2,6-bisphosphate. Comparisons of the simulations of the large 240 kDa apo and holo tetramers show that binding of fructose 2,6-bisphosphate cools the enzyme and reduces dynamic movement, particularly of the B-domain. The reduced dynamic movement of the holo form traps the pyruvate kinase tetramer in its enzymatically active state with the B-domain acting as a lid to cover the active site. The simulations are also consistent with a transition of the mobile active-site α6' helix, which would adopt a helical conformation in the active R-state and a less structured coil conformation in the inactive T-state. Analysis of the rigid body motions over the trajectory highlights the concerted anticorrelated rigid body rocking motion of the four protomers, which drives the T to R transition. The transitions predicted by these simulations are largely consistent with the Monod-Wyman-Changeux model for allosteric activation but also suggest that rigidification or cooling of the overall structure upon effector binding plays an additional role in enzyme activation.
    MeSH term(s) Allosteric Regulation ; Fructosediphosphates/metabolism ; Leishmania mexicana ; Molecular Dynamics Simulation ; Motion ; Protein Multimerization ; Protein Structure, Secondary ; Protozoan Proteins/metabolism ; Pyruvate Kinase/metabolism
    Chemical Substances Fructosediphosphates ; Protozoan Proteins ; fructose 2,6-diphosphate (79082-92-1) ; Pyruvate Kinase (EC 2.7.1.40)
    Language English
    Publishing date 2015-09-15
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218078-9
    ISSN 1542-0086 ; 0006-3495
    ISSN (online) 1542-0086
    ISSN 0006-3495
    DOI 10.1016/j.bpj.2015.05.040
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    Zs.A 235: Show issues Location:
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    Zs.MO 2: Show issues

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  9. Article ; Online: Oligopeptide Signaling through TbGPR89 Drives Trypanosome Quorum Sensing.

    Rojas, Federico / Silvester, Eleanor / Young, Julie / Milne, Rachel / Tettey, Mabel / Houston, Douglas R / Walkinshaw, Malcolm D / Pérez-Pi, Irene / Auer, Manfred / Denton, Helen / Smith, Terry K / Thompson, Joanne / Matthews, Keith R

    Cell

    2018  Volume 176, Issue 1-2, Page(s) 306–317.e16

    Abstract: Trypanosome parasites control their virulence and spread by using quorum sensing (QS) to generate transmissible "stumpy forms" in their host bloodstream. However, the QS signal "stumpy induction factor" (SIF) and its reception mechanism are unknown. ... ...

    Abstract Trypanosome parasites control their virulence and spread by using quorum sensing (QS) to generate transmissible "stumpy forms" in their host bloodstream. However, the QS signal "stumpy induction factor" (SIF) and its reception mechanism are unknown. Although trypanosomes lack G protein-coupled receptor signaling, we have identified a surface GPR89-family protein that regulates stumpy formation. TbGPR89 is expressed on bloodstream "slender form" trypanosomes, which receive the SIF signal, and when ectopically expressed, TbGPR89 drives stumpy formation in a SIF-pathway-dependent process. Structural modeling of TbGPR89 predicts unexpected similarity to oligopeptide transporters (POT), and when expressed in bacteria, TbGPR89 transports oligopeptides. Conversely, expression of an E. coli POT in trypanosomes drives parasite differentiation, and oligopeptides promote stumpy formation in vitro. Furthermore, the expression of secreted trypanosome oligopeptidases generates a paracrine signal that accelerates stumpy formation in vivo. Peptidase-generated oligopeptide QS signals being received through TbGPR89 provides a mechanism for both trypanosome SIF production and reception.
    MeSH term(s) Cell Differentiation ; Conserved Sequence/genetics ; GTP-Binding Proteins/metabolism ; Membrane Transport Proteins/genetics ; Membrane Transport Proteins/physiology ; Oligopeptides/genetics ; Oligopeptides/physiology ; Phylogeny ; Protozoan Proteins/metabolism ; Quorum Sensing/genetics ; Quorum Sensing/physiology ; Signal Transduction ; Trypanosoma/metabolism ; Trypanosoma/physiology ; Trypanosoma brucei brucei/metabolism ; Trypanosomiasis, African/parasitology ; Virulence/physiology
    Chemical Substances Membrane Transport Proteins ; Oligopeptides ; Protozoan Proteins ; peptide permease (97599-47-8) ; GTP-Binding Proteins (EC 3.6.1.-)
    Language English
    Publishing date 2018-11-29
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2018.10.041
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  10. Article: Dynamic design: manipulation of millisecond timescale motions on the energy landscape of cyclophilin A.

    Juárez-Jiménez, Jordi / Gupta, Arun A / Karunanithy, Gogulan / Mey, Antonia S J S / Georgiou, Charis / Ioannidis, Harris / De Simone, Alessio / Barlow, Paul N / Hulme, Alison N / Walkinshaw, Malcolm D / Baldwin, Andrew J / Michel, Julien

    Chemical science

    2020  Volume 11, Issue 10, Page(s) 2670–2680

    Abstract: ... broadly unchanged. These predictions are confirmed using CPMG and R ...

    Abstract Proteins need to interconvert between many conformations in order to function, many of which are formed transiently, and sparsely populated. Particularly when the lifetimes of these states approach the millisecond timescale, identifying the relevant structures and the mechanism by which they interconvert remains a tremendous challenge. Here we introduce a novel combination of accelerated MD (aMD) simulations and Markov state modelling (MSM) to explore these 'excited' conformational states. Applying this to the highly dynamic protein CypA, a protein involved in immune response and associated with HIV infection, we identify five principally populated conformational states and the atomistic mechanism by which they interconvert. A rational design strategy predicted that the mutant D66A should stabilise the minor conformations and substantially alter the dynamics, whereas the similar mutant H70A should leave the landscape broadly unchanged. These predictions are confirmed using CPMG and R
    Language English
    Publishing date 2020-01-15
    Publishing country England
    Document type Journal Article
    ZDB-ID 2559110-1
    ISSN 2041-6539 ; 2041-6520
    ISSN (online) 2041-6539
    ISSN 2041-6520
    DOI 10.1039/c9sc04696h
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