ORCID Profile
0000-0002-5368-937X
Current Organisations
University of Western Australia
,
University of Oxford
,
University of Adelaide
,
Flinders Medical Centre
,
InterX
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Publisher: Elsevier
Date: 2011
Publisher: Public Library of Science (PLoS)
Date: 15-10-2015
Publisher: Elsevier BV
Date: 09-2014
Publisher: Springer Science and Business Media LLC
Date: 26-09-2016
DOI: 10.1038/SREP33958
Abstract: The rugged folding landscapes of functional proteins puts them at risk of misfolding and aggregation. Serine protease inhibitors, or serpins, are paradigms for this delicate balance between function and misfolding. Serpins exist in a metastable state that undergoes a major conformational change in order to inhibit proteases. However, conformational labiality of the native serpin fold renders them susceptible to misfolding, which underlies misfolding diseases such as α 1 -antitrypsin deficiency. To investigate how serpins balance function and folding, we used consensus design to create conserpin, a synthetic serpin that folds reversibly, is functional, thermostable and polymerization resistant. Characterization of its structure, folding and dynamics suggest that consensus design has remodeled the folding landscape to reconcile competing requirements for stability and function. This approach may offer general benefits for engineering functional proteins that have risky folding landscapes, including the removal of aggregation-prone intermediates and modifying scaffolds for use as protein therapeutics.
Publisher: Cold Spring Harbor Laboratory
Date: 14-12-2017
DOI: 10.1101/234260
Abstract: Abacavir is an antiretroviral drug used to reduce human immunodeficiency virus (HIV) replication and decrease the risk of developing acquired immune deficiency syndrome (AIDS). However, its therapeutic value is diminished by the fact that it is associated with drug hypersensitivity reactions in up to 8% of treated patients. This hypersensitivity is strongly associated with patients carrying human leukocyte antigen (HLA)-B*57:01, but not patients carrying closely related alleles. Abacavir’s specificity to HLA-B*57:01 is attributed to its binding site within the peptide-binding cleft and subsequent influence of the repertoire of peptides that can bind HLA-B*57:01. To further our understanding of abacavir-induced hypersensitivity we used molecular dynamics (MD) to analyze the dynamics of three different peptides bound to HLA-B*57:01 in the presence and absence of abacavir or abacavir analogues. We found that abacavir and associated peptides bind to HLA-B*57:01 in a highly erse range of conformations that are not apparent from static crystallographic snapshots. Further, the presence of abacavir has a direct impact on the dynamics and the conformational space available to peptides bound to HLA-B*57:01, likely influencing abacavir-induced immune self-reactivity. Our results support hypersensitivity models in which abacavir-binding alters the equilibrium proportions of neopeptide conformations in a manner favourable to TCR binding. Our findings highlight the need to also consider the role of dynamics in understanding drug-induced hypersensitivities at the molecular and mechanistic level. This additional insight can help inform the chemical modification of abacavir to prevent hypersensitivity reactions in HLA-B*57:01+ HIV patients whilst retaining potent antiretroviral activity.
Publisher: Springer Science and Business Media LLC
Date: 23-11-2020
DOI: 10.1186/S13244-020-00936-W
Abstract: To identify the 100 top-cited meta-analyses of diagnostic accuracy studies published in radiology, medical imaging and nuclear medicine journals. A PubMed search with pre-defined criteria was performed. The 100 top-cited articles meta-analyses were retrieved, using a custom Python script and the Scopus Application Programming Interface (Elsevier). Publication, citation and affiliation details were extracted from each meta-analysis. No formal statistical analysis was performed. The top meta-analysis was cited 394 times, the 100th meta-analysis 38 times. The USA was the top country represented in the papers (33 meta-analyses) followed by The Netherlands, China and Germany. The journal Radiology published 24 studies. The most common modality reported was positron emission tomography (PET) or PET computed tomography (36 instances), followed by magnetic resonance imaging (30 instances) and computed tomography (27 instances). Cardiac (19 meta-analyses), abdominal (18 meta-analyses), followed by neurological (12 meta-analyses) investigations were the most frequently encountered in the top 100 cited meta-analyses. The 100 top-cited meta-analyses encompass a broad range of imaging modalities and body regions. This may comprise a useful resource for identifying influential evidence-based diagnostic accuracy information in radiology.
Publisher: Elsevier BV
Date: 06-2012
Publisher: Wiley
Date: 09-11-2018
Abstract: The M1 metallo-aminopeptidase from Plasmodium falciparum, PfA-M1, is an attractive drug target for the design of new antimalarials. Bestatin, a broad-spectrum metalloprotease inhibitor, is a moderate inhibitor of PfA-M1, and has been used to provide structure-activity relationships to inform drug design. The crystal structure of PfA-M1 with bestatin bound within its active site has been determined however, dynamics of the inhibitor and the association or dissociation pathway have yet to be characterized. Here we present an all-atom molecular dynamics study where we have generated a hidden Markov state model from 2.3 μs of molecular dynamics simulation. Our hidden Markov state model identifies five macrostates that clearly show the events involved in bestatin dissociation from the PfA-M1 active site. The results show for the first time that bestatin can escape the substrate specificity pockets of the enzyme, primarily due to weak interactions within the pockets. Our approach identifies relevant conformational s ling of the inhibitor inside the enzyme and the protein dynamics that could be exploited to produce potent and selective inhibitors that can differentiate between similar members of the M1 aminopeptidase superfamily.
Publisher: Elsevier BV
Date: 05-2023
Publisher: Springer Science and Business Media LLC
Date: 29-06-2023
DOI: 10.1038/SREP35385
Abstract: The kallikrein-related peptidase (KLK) family of proteases is involved in many aspects of human health and disease. One member of this family, KLK4, has been implicated in cancer development and metastasis. Understanding mechanisms of inactivation are critical to developing selective KLK4 inhibitors. We have determined the X-ray crystal structures of KLK4 in complex with both sunflower trypsin inhibitor-1 (SFTI-1) and a rationally designed SFTI-1 derivative to atomic (~1 Å) resolution, as well as with bound nickel. These structures offer a structural rationalization for the potency and selectivity of these inhibitors, and together with MD simulation and computational analysis, reveal a dynamic pathway between the metal binding exosite and the active site, providing key details of a previously proposed allosteric mode of inhibition. Collectively, this work provides insight into both direct and indirect mechanisms of inhibition for KLK4 that have broad implications for the enzymology of the serine protease superfamily, and may potentially be exploited for the design of therapeutic inhibitors.
Publisher: Proceedings of the National Academy of Sciences
Date: 09-06-2014
Abstract: Autoimmune type 1 diabetes is characterized by the formation of self-reactive antibodies. A prevalent human autoantigen is glutamate decarboxylase (GAD)65, a highly predictive marker that can precede the emergence of disease by up to several years. Intriguingly, the closely related isoform GAD67 is not immunogenic. What are the determinants of the unique self-reactivity of GAD65 vs. GAD67? We show that, unlike GAD67, GAD65 is highly flexible and exists in multiple structural forms. We show that self-antibodies bind differentially to these GAD65 forms. These properties may be an undesirable consequence of conformational flexibility necessary for enzyme function. Our findings, thus, provide insights into how structural flexibility governs protein immunogenicity in autoimmune diabetes and have implications for therapeutic antibody and vaccine design.
Publisher: SAGE Publications
Date: 2020
Abstract: An unusual case of infectious mononucleosis complicated by both peritonsillar abscess and postural orthostatic tachycardia syndrome is reported. The patient was diagnosed with Epstein–Barr virus infection early in the disease course by her primary care doctor. She subsequently developed a peritonsillar abscess requiring hospitalisation. Recovery was complicated by the development of postural orthostatic tachycardia syndrome. However, resolution was achieved over the course of approximately 1 year, via conservative measures including graded exercise therapy, without resorting to pharmacotherapy.
Publisher: Public Library of Science (PLoS)
Date: 12-2015
Publisher: Wiley
Date: 04-12-2018
Publisher: Cold Spring Harbor Laboratory
Date: 22-02-2018
DOI: 10.1101/269613
Abstract: Canonical mechanisms of protein evolution include the duplication and ersification of pre-existing folds through genetic alterations that include point mutations, insertions, deletions, and copy number lifications, as well as post-translational modifications that modify processes such as folding efficiency and cellular localization. Following a survey of the human mutation database, we have identified an additional mechanism, that we term ‘structural capacitance’, which results in the de novo generation of microstructure in previously disordered regions. We suggest that the potential for structural capacitance confers select proteins with the capacity to evolve over rapid timescales, facilitating saltatory evolution as opoposed to exclusively canonical Darwinian mechanisms. Our results implicate the elements of protein microstructure generated by this distinct mechanism in the pathogenesis of a wide variety of human diseases. The benefits of rapidly furnishing the potential for evolutionary change conferred by structural capacitance are consequently counterbalanced by this accompanying risk, with the extent of this determined by the host immune system. The phenomenon of structural capacitance has implications ranging from the ancestral ersification of protein folds to the engineering of synthetic proteins with enhanced evolvability.
Publisher: Elsevier BV
Date: 07-2022
Publisher: Cold Spring Harbor Laboratory
Date: 15-06-2020
DOI: 10.1101/2020.06.14.151373
Abstract: Mutation of cytochrome c in humans causes mild autosomal dominant thrombocytopenia. The role of cytochrome c in platelet formation, and molecular mechanism underlying the association of cytochrome c mutations with thrombocytopenia remains unknown, although a gain-of-function is most likely. Cytochrome c contributes to several cellular processes, with exchange between conformational states proposed to regulate changes in function. Here we use experimental and computational approaches to determine whether pathogenic variants share changes in structure and function, and to understand how these changes might occur. We find that three pathogenic variants (G41S, Y48H, A51V) cause an increase in apoptosome activation and peroxidase activity. Molecular dynamics simulations of these variants, and two non-naturally occurring variants (G41A, G41T), indicate that increased apoptosome activation correlates with increased overall flexibility of cytochrome c , particularly movement of the Ω loops. This suggests that the binding of cytochrome c to apoptotic protease activating factor-1 (Apaf-1) may involve an “induced fit” mechanism which is enhanced in the more conformationally mobile variants. In contrast, peroxidase activity did not significantly correlate with protein dynamics suggesting that the mechanism by which the variants alter peroxidase activity is not related to the conformation dynamics of the hexacoordinate heme Fe state of cytochrome c analyzed in the simulations. Recent suggestions that conformational mobility of specific regions of cytochrome c underpins changes in reduction potential and the alkaline transition p K were not supported. These data highlight that conformational dynamics of cytochrome c drives some but not all of its properties and activities.
Publisher: Elsevier BV
Date: 10-2008
DOI: 10.1016/J.JMB.2008.07.034
Abstract: Class I hydrophobins are fungal proteins that self-assemble into robust hipathic rodlet monolayers on the surface of aerial structures such as spores and fruiting bodies. These layers share many structural characteristics with amyloid fibrils and belong to the growing family of functional amyloid-like materials produced by microorganisms. Although the three-dimensional structure of the soluble monomeric form of a class I hydrophobin has been determined, little is known about the molecular structure of the rodlets or their assembly mechanism. Several models have been proposed, some of which suggest that the Cys3-Cys4 loop has a critical role in the initiation of assembly or in the polymeric structure. In order to provide insight into the relationship between hydrophobin sequence and rodlet assembly, we investigated the role of the Cys3-Cys4 loop in EAS, a class I hydrophobin from Neurospora crassa. Remarkably, deletion of up to 15 residues from this 25-residue loop does not impair rodlet formation or reduce the surface activity of the protein, and the physicochemical properties of rodlets formed by this mutant are indistinguishable from those of its full-length counterpart. In addition, the core structure of the truncation mutant is essentially unchanged. Molecular dynamics simulations carried out on the full-length protein and this truncation mutant binding to an air-water interface show that, although it is hydrophobic, the loop does not play a role in positioning the protein at the surface. These results demonstrate that the Cys3-Cys4 loop does not have an integral role in the formation or structure of the rodlets and that the major determinant of the unique properties of these proteins is the hipathic core structure, which is likely to be preserved in all hydrophobins despite the high degree of sequence variation across the family.
Publisher: Springer Science and Business Media LLC
Date: 19-07-2019
DOI: 10.1038/S41598-019-47001-1
Abstract: Abacavir is an antiretroviral drug used to reduce human immunodeficiency virus (HIV) replication and decrease the risk of developing acquired immune deficiency syndrome (AIDS). However, its therapeutic value is diminished by the fact that it is associated with drug hypersensitivity reactions in up to 8% of treated patients. This hypersensitivity is strongly associated with patients carrying human leukocyte antigen (HLA)-B*57:01, but not patients carrying closely related alleles. Abacavir’s specificity to HLA-B*57:01 is attributed to its binding site within the peptide-binding cleft and subsequent influence of the repertoire of peptides that can bind HLA-B*57:01. To further our understanding of abacavir-induced hypersensitivity we used molecular dynamics (MD) to analyze the dynamics of three different peptides bound to HLA-B*57:01 in the presence and absence of abacavir or abacavir analogues. We found that abacavir and associated peptides bind to HLA-B*57:01 in a highly erse range of conformations that are not apparent from static crystallographic snapshots, but observed no difference in either the conformations, nor degree of flexibility when compared to abacavir-unbound systems. Our results support hypersensitivity models in which abacavir-binding alters the conformational ensemble of neopeptides, so as to favour exposed peptide surfaces that are no longer recognized as self by circulating CD8+ T cells, and are conducive to TCR binding. Our findings highlight the need to also consider the role of dynamics in understanding drug-induced hypersensitivities at the molecular and mechanistic level. This additional insight can help inform the chemical modification of abacavir to prevent hypersensitivity reactions in HLA-B*57:01+ HIV patients whilst retaining potent antiretroviral activity.
Publisher: Elsevier BV
Date: 05-2013
Location: United Kingdom of Great Britain and Northern Ireland
Location: Israel
No related grants have been discovered for Itamar Kass.