Dissociation of an antiviral compound from the internal pocket of human rhinovirus 14 capsid

Li, Yumin; Zhou, Zhigang; Post, Carol Beth

doi:10.1073/pnas.0408749102

Cited by 17 publications

(20 citation statements)

References 30 publications

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“…A better understanding of the insertion and passage of the lipophilic Q/QH2 through the portal could be gained through molecular dynamics analysis, as studied in the passage of ubiquinone through a defect in the ring of light-harvesting (LHI) bacteriochlorophyll molecules surrounding the photosynthetic reaction center (234), and the insertion of a drug molecule into a virus capsid protein (235), which has a formal resemblance to quinol insertion into the p-side entry portal to the [2Fe-2S] cluster. The combination of kinetic and steric constraints of portal entry-extrusion of quinol/quinone in the most frequent description of the Q cycle, described symbolically in Fig.…”

Section: The Problem Of the P-side Portalmentioning

confidence: 99%

The Q cycle of cytochrome bc complexes: A structure perspective

Cramer

Hasan

Yamashita

2011

Biochimica et Biophysica Acta (BBA) - Bioenergetics

157

159

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Summary Aspects of the crystal structures of the hetero-oligomeric cytochrome bc1 and b6f (“bc”) complexes relevant to their electron/proton transfer function and the associated redox reactions of the lipophilic quinones are discussed. Differences between the b6f and bc1 complexes are emphasized. The cytochrome bc1 and b6f dimeric complexes diverge in structure from a core of subunits that coordinate redox groups consisting of two bis-histidine coordinated hemes, a heme bn and bp on the electrochemically negative (n) and positive (p) sides of the complex, the high potential [2Fe-2S] cluster and c-type heme at the p-side aqueous interface and aqueous phase, respectively, and quinone/quinol binding sites on the n- and p-sides of the complex. The bc1 and b6f complexes diverge in subunit composition and structure away from this core. b6f also contains additional prosthetic groups including a c-type heme cn on the n-side, and a chlorophyll a and β-carotene. Common structure aspects; functions of the symmetric dimer. (I) Quinone exchange with the bilayer. An inter-monomer protein-free cavity of approximately 30 Å along the membrane normal × 25 Å (central inter-monomer distance) × 15 Å (depth in the center), is common to both bc1 and b6f complexes, providing a niche in which the lipophilic quinone/quinol (Q/QH2) can be exchanged with the membrane bilayer. (II) Electron transfer. The dimeric structure and the proximity of the two hemes bp on the electrochemically positive side of the complex in the two monomer units allow the possibility of two alternate routes of electron transfer across the complex from heme bp to bn,: intra-monomer, and inter-monomer involving electron cross-over between the two hemes bp. A structure-based summary of inter-heme distances in seven bc complexes, representing mitochondrial, chromatophore, cyanobacterial, and algal sources, indicates that, based on the distance parameter, the intra-monomer pathway would be favored kinetically. (III) Separation of quinone binding sites. A consequence of the dimer structure and the position of the Q/QH2binding sites is that the p-side QH2 oxidation and n-side Q reduction sites are each well separated. Therefore, In the event of an overlap in residence time by QH2 or Q molecules at the two oxidation or reduction sites, their spatial separation would result in minimal steric interference between extended Q or QH2 isoprenoid chains. (IV) Trans-membrane QH2/Q transfer. (i) n/p side QH2/Q transfer may be hindered by lipid acyl chains; (ii) the shorter less hindered inter-monomer pathway across the complex would not pass through the center of the cavity, as inferred from the n-side antimycin site on one monomer and the p-side stigmatellin site on the other residing on the same surface of the complex. (V) Narrow p-Side portal for QH2/Q passage. The [2Fe-2S] cluster that serves as oxidant, and whose hisitidine ligand serves as a H+ acceptor in the oxidation of QH2, is connected to the inter-monomer cavity by a narrow extended portal, which is also occupied in the ...

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Section: The Problem Of the P-side Portalmentioning

confidence: 99%

The Q cycle of cytochrome bc complexes: A structure perspective

Cramer

Hasan

Yamashita

2011

Biochimica et Biophysica Acta (BBA) - Bioenergetics

157

159

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“…The method was introduced by Pettitt over 20 years ago, but has seen limited usage. The major proponents of the method have been May and Brooks[49, 54–57] and Post[58–61]. …”

Section: All-atom Modelingmentioning

confidence: 99%

Recent developments in molecular simulation approaches to study spherical virus capsids

May

2014

Molecular Simulation

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Viruses are a particularly challenging systems to study via molecular simulation methods. Virus capsids typically consist of over 100 subunit proteins and reach dimensions of over 100 nm; solvated viruses capsid systems can be over 1 million atoms in size. In this review, I will present recent developments which have attempted to overcome the significant computational expense to perform simulations which can inform experimental studies, make useful predictions about biological phenomena and calculate material properties relevant to nanotechnology design efforts.

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“…Thus, all five structural elements that the neutralizing VHHs bind in common (possibly except for the distal GH loop of VP1) lie in direct contact either with the pocket factor itself or with hydrophobic residues that line the pocket. Computational dynamics simulations by Li et al (32) on a complex between rhinovirus 14 and the capsid-binding drug WIN52084 showed that the pocket occupant can snake its way out of the pore (the outer, hydrophilic open end of the pocket) without significantly perturbing the native virus structure, except in three specific, localized areas of VP1. These areas included the C beta strand and the EF loop (both of which are common VHH contact areas) and the middle of the G beta strand.…”

Section: Figmentioning

confidence: 99%

Five of Five VHHs Neutralizing Poliovirus Bind the Receptor-Binding Site

Strauß

Schotte

Thys

et al. 2016

J Virol

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Nanobodies, or VHHs, that recognize poliovirus type 1 have previously been selected and characterized as candidates for antiviral agents or reagents for standardization of vaccine quality control. In this study, we present high-resolution cryo-electron microscopy reconstructions of poliovirus with five neutralizing VHHs. All VHHs bind the capsid in the canyon at sites that extensively overlap the poliovirus receptor-binding site. In contrast, the interaction involves a unique (and surprisingly extensive) surface for each of the five VHHs. Five regions of the capsid were found to participate in binding with all five VHHs. Four of these five regions are known to alter during the expansion of the capsid associated with viral entry. Interestingly, binding of one of the VHHs, PVSS21E, resulted in significant changes of the capsid structure and thus seems to trap the virus in an early stage of expansion. IMPORTANCEWe describe the cryo-electron microscopy structures of complexes of five neutralizing VHHs with the Mahoney strain of type 1 poliovirus at resolutions ranging from 3.8 to 6.3Å. In addition to conventional antibodies, members of the Camelidae family possess a set of unusual antibodies that consist only of heavy chains in which a constant domain is missing and that are therefore named heavy-chain-only antibodies (1). These antibodies offer a very interesting new tool in scientific research, as they contain variable domains (VHHs) that are fully responsible for and fully capable of recognizing and binding to antigens. The variable domains are also more hydrophilic than their IgG counterparts, as they are not required to bind to a complementary domain of a light chain. Moreover, they are very stable (2), and due to their rather small size (ϳ14 kDa), they are able to bind to epitopes within clefts (3) that are more difficult to reach for larger antibodies. Both their single-domain nature and their lack of glycosylation allow them to be produced at high levels using bacterial expression systems.Motivated by searches for potential antiviral agents, VHHs that specifically bind to and neutralize poliovirus type 1 were recently selected and identified (4) and were further characterized (5, 6). In a previous publication (5), we showed that the binding footprints of two VHHs (PVSP6A and PVSP29F) on the poliovirus surface overlap extensively with the footprint of the poliovirus receptor (PVR; also called CD155) and that they produce well-ordered icosahedrally symmetric complexes. It was also shown that the mechanisms of neutralization operate at multiple stages of the infection process and that all of the neutralizing VHHs stabilize the virus to prevent viral expansion (5), which is an essential step in the infection of cells.As a member of the Picornaviridae family, poliovirus is a naked virus comprised only of a protein capsid surrounding its positively single-stranded RNA. The capsid has a pseudo Tϭ3 icosahedral surface with 60 copies of each of four viral proteins (VPs), VP1 to VP4, of which VP4, the smalles...

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Dissociation of an antiviral compound from the internal pocket of human rhinovirus 14 capsid

Cited by 17 publications

References 30 publications

The Q cycle of cytochrome bc complexes: A structure perspective

The Q cycle of cytochrome bc complexes: A structure perspective

Recent developments in molecular simulation approaches to study spherical virus capsids

Five of Five VHHs Neutralizing Poliovirus Bind the Receptor-Binding Site

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