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SUMMARY:A Two-pronged Attack: Dual Inhibition of Plasmodium falciparum M1 
 and M17 Metalloaminopeptidases by a Novel Series of Hydroxamic acid-based 
 Inhibitors.
DTSTART;VALUE=DATE-TIME:20141121T004500Z
DTEND;VALUE=DATE-TIME:20141121T010500Z
DTSTAMP;VALUE=DATE-TIME:20260809T081726Z
UID:indico-contribution-208-765@events01.synchrotron.org.au
DESCRIPTION:Speakers: Nyssa Drinkwater (Monash University)\nMalaria is cau
 sed by parasites of the genus Plasmodium\, with Plasmodium falciparum (Pf)
  causing the most deaths. The prevention and treatment of Pf malaria is be
 coming increasingly difficult due to the spread of drug resistant parasite
 s. New therapeutics with a novel mode of action are desperately required. 
 Two Plasmodium falciparum aminopeptidases\, PfA-M1 and PfA-M17\, play cruc
 ial roles in the erythrocytic stage of infection\, and have been validated
  as potential antimalarial targets. Using compound-bound crystal structure
 s of both enzymes\, we were able to identify key similarities and differen
 ces in the mechanism of inhibitor binding by PfA-M1 versus PfA-M17\, which
  we exploited to design inhibitors capable of potently inhibiting both enz
 ymes. The resultant hydroxamic acid-based inhibitors represent the first c
 ompounds capable of potent dual inhibition of both PfA-M1 and PfA-M17. The
  compounds additionally possess nanomolar activity against 3D7 malaria par
 asites and no observable cytotoxicity\, and are therefore extremely attrac
 tive lead molecules for further development into antimalarial therapeutics
  with a novel mode of action.\n\nhttps://events01.synchrotron.org.au/event
 /3/contributions/765/
LOCATION: Oliphant Auditorium
URL:https://events01.synchrotron.org.au/event/3/contributions/765/
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SUMMARY:Structural Studies of Alzheimer’s Disease Amyloid Precursor Prot
 ein Dimers
DTSTART;VALUE=DATE-TIME:20141121T010500Z
DTEND;VALUE=DATE-TIME:20141121T012500Z
DTSTAMP;VALUE=DATE-TIME:20260809T081726Z
UID:indico-contribution-208-764@events01.synchrotron.org.au
DESCRIPTION:Speakers: Chen Gao (Structural Biology Laboratory and ACRF Rat
 ional Drug Discovery Centre\, St Vincent's Institute of Medical Research\,
  University of Melbourne\, Melbourne\, Vic\, Australia)\nAmyloid precursor
  protein (APP) is a type-I transmembrane protein with a large ectodomain (
 sAPP)\, a single transmembrane domain and a cytoplasmic tail. It is cleave
 d by beta- and gamma-secretases to generate amyloid-β (Aβ)\, a neurotoxi
 c peptide implicated in Alzheimer’s disease (AD). APP dimerisation is cl
 osely linked to Aβ overproduction. It is also implicated in APP signallin
 g as APP is proposed to be membrane receptor. There are four potential dim
 erisation sites in APP\, three of which are located in the sAPP region. Ho
 wever\, the mechanism of APP dimerisation remains unclear. Understanding A
 PP dimerisation mechanisms at the molecular level will not only provide in
 sights into how APP signals but also have therapeutic implications. Severa
 l factors are found to regulate APP proteolysis in vivo. To test their imp
 act on sAPP dimerisation\, we used in vitro techniques including ThermoFlu
 or\, analytical ultracentrifugation and multi-angle light scattering. We f
 ound certain metals and sugars synergistically drive sAPP dimerisation\, w
 hich is associated with conformational changes and increased stability. Th
 is discovery has led to the successful crystallisation of sAPP in its dime
 ric forms. The identities of metal ions were confirmed using anomalous dif
 ference Fourier maps. Key features underlying sAPP dimer formation are cle
 arly demonstrated in the structure. Together with results from the solutio
 n studies\, the crystal structure has provided a leap forward in understan
 ding the mechanism of APP dimerisation and its pathogenic and functional i
 mplications. The structure will be used to discover inhibitors of APP dime
 risation and Aβ overproduction as possible AD therapeutics.\n\nhttps://ev
 ents01.synchrotron.org.au/event/3/contributions/764/
LOCATION: Oliphant Auditorium
URL:https://events01.synchrotron.org.au/event/3/contributions/764/
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SUMMARY:Structural insights into the organization of the cavin membrane co
 at
DTSTART;VALUE=DATE-TIME:20141121T001500Z
DTEND;VALUE=DATE-TIME:20141121T004500Z
DTSTAMP;VALUE=DATE-TIME:20260809T081726Z
UID:indico-contribution-208-705@events01.synchrotron.org.au
DESCRIPTION:Speakers: Brett Collins (The University of Queensland\, Instit
 ute for Molecular Bioscience)\nCaveola membrane invaginations are a striki
 ng feature of many vertebrate cell types\, and are critical for cell signa
 ling\, endocytosis and mechanotransduction. Their formation depends on the
  caveolins and the cavin peripheral membrane proteins (cavin1\, cavin2\, c
 avin3 and cavin4)\, although there is currently no atomic level informatio
 n addressing the mechanisms that underpin caveola assembly. Here we show t
 hat a minimal N-terminal domain of the cavin proteins (the HR1 fragment) i
 s required and sufficient for their homo and hetero-oligomerisation. The c
 rystal structures of mouse cavin1 and zebrafish cavin4 HR1 domains reveal 
 highly conserved trimeric coiled-coil architectures\, with unique intra-su
 bunit interactions that determine the specificity of coiled-coil formation
 . A conspicuous feature of the HR1 domain is a basic surface patch\, conse
 rved among all cavins and across all species\, which we show can mediate i
 nteraction with negatively-charged membrane lipids including phosphoinosit
 ides. Mutations in this domain prevent membrane association and perturb ca
 veolae formation in vivo. Interestingly the cavin proteins possess intrins
 ic membrane remodeling properties in vitro\, that we propose is important 
 for the formation of caveolae. Finally\, we show that full-length cavin pr
 oteins possess characteristic rod-shape structures that reflect the coiled
 -coil architecture of the HR1 assembly domain and have dimensions correspo
 nding closely to the striations observed on the surface of caveolae in viv
 o. We therefore propose the striations forming the common coat of caveola 
 are composed of polymerised cavin trimers.\n\nhttps://events01.synchrotron
 .org.au/event/3/contributions/705/
LOCATION: Oliphant Auditorium
URL:https://events01.synchrotron.org.au/event/3/contributions/705/
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SUMMARY:Crystal Structure of Human Insulin-Regulated Aminopeptidase
DTSTART;VALUE=DATE-TIME:20141121T012500Z
DTEND;VALUE=DATE-TIME:20141121T014500Z
DTSTAMP;VALUE=DATE-TIME:20260809T081726Z
UID:indico-contribution-208-670@events01.synchrotron.org.au
DESCRIPTION:Speakers: Stefan Hermans (St Vincent's Institute)\nDementia is
  the single greatest cause of disability in older Australians afflicting a
 lmost one in ten over the age of 65. In the absence of curative therapies\
 , current treatments aimed at enhancing working memory target the choliner
 gic system and demonstrate limited efficacy\, underpinning the need for a 
 new class of cognitive enhancing drug. Insulin-regulated aminopeptidase (I
 RAP) is a membrane-bound zinc-metallopeptidase that cleaves neuroactive pe
 ptides in the brain and its inhibition gives rise to memory enhancing effe
 cts in both normal and memory-impaired rodents . Using a large scale insec
 t cell expression system to produce milligram quantities of protein suitab
 le for crystallography\, and the Micro Crystallography Beamline at the Aus
 tralian Synchrotron\, we have determined the crystal structure of human IR
 AP to 2.96 Å. This structure revealed a semi-closed\, four domain arrange
 ment with a large\, mostly buried cavity adjacent to the active site as we
 ll as a dimer interface located in the C-terminal domain. A comparison of 
 the catalytic domain with related aminopeptidases revealed a strikingly di
 fferent conformation of the GAMEN exopeptidase loop that explains IRAP’s
  unique specificity for cyclic peptides such as oxytocin and vasopressin. 
 This structure will be a powerful tool in the development of new classes o
 f cognitive enhancers for treating memory disorders such as Alzheimer's de
 mentia.\n\nhttps://events01.synchrotron.org.au/event/3/contributions/670/
LOCATION: Oliphant Auditorium
URL:https://events01.synchrotron.org.au/event/3/contributions/670/
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