Energetics of the loop‐to‐helix transition leading to the coiled‐coil structure of influenza virus hemagglutinin HA2 subunits

Huang, Qiang; Korte, Thomas; Rachakonda, P. Sivaramakrishna; Knapp, Ernst‐Walter; Herrmann, Andreas

doi:10.1002/prot.22157

Cited by 17 publications

(19 citation statements)

References 70 publications

(54 reference statements)

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“…In order to drive the loop-to-helix transition and the formation of a coiled-coil structure, it is necessary for water molecules to directly interact with the hydrophilic residues 15 . Therefore, the ability of INT to stabilize the connection between HA1 and HA2 and to effectively prevent water from entering into the interior of HA2 is crucial for the inhibitory activity of INT.…”

Section: Resultsmentioning

confidence: 99%

Exploration of binding and inhibition mechanism of a small molecule inhibitor of influenza virus H1N1 hemagglutinin by molecular dynamics simulation

Guan

Wang

Kuai

et al. 2017

Sci Rep

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Influenza viruses are a major public health threat worldwide. The influenza hemagglutinin (HA) plays an essential role in the virus life cycle. Due to the high conservation of the HA stem region, it has become an especially attractive target for inhibitors for therapeutics. In this study, molecular simulation was applied to study the mechanism of a small molecule inhibitor (MBX2329) of influenza HA. Behaviors of the small molecule under neutral and acidic conditions were investigated, and an interesting dynamic binding mechanism was found. The results suggested that the binding of the inhibitor with HA under neutral conditions facilitates only its intake, while it interacts with HA under acidic conditions using a different mechanism at a new binding site. After a series of experiments, we believe that binding of the inhibitor can prevent the release of HA1 from HA2, further maintaining the rigidity of the HA2 loop and stabilizing the distance between the long helix and short helices. The investigated residues in the new binding site show high conservation, implying that the new binding pocket has the potential to be an effective drug target. The results of this study will provide a theoretical basis for the mechanism of new influenza virus inhibitors.Influenza virus is the causative agent of influenza, an infectious disease which usually leads to symptoms such as high fever, cough, headache, muscle and joint pain, sore throat, nasal discharge, and even a fatal illness similar to pneumonia 1-4 . Influenza viruses are divided into three types, type A, type B and type C, with influenza A virus presenting serious threats to public health worldwide due to its high mutation rate [5][6][7] . At present, two classes of drugs are approved by the Food and Drug Administration for treatment or chemoprophylaxis of influenza: matrix protein 2 (M2) inhibitors amantadine and rimantadine and the neuraminidase (NA) inhibitors (NAIs) oseltamivir and zanamivir 8,9 . However, with the wide use of these drugs, drug-resistant strains have appeared in succession 10 . Therefore, new antiviral targets with novel inhibition mechanism need to be developed.Hemagglutinin (HA), a viral receptor-binding and membrane-fusion glycoprotein involved in the invasion of influenza into host cells, plays an essential role in the life cycle of influenza A virus 3,11 . HA is a trimer of identical subunits, each of which consists of a variable membrane-distal receptor-binding globular domain (HA1) and a more conserved membrane-proximal helix-rich stem structure (HA2) 12 . Under acidic conditions, the residues on the outer surface of HA1 can be protonated easily, which leads to the large gathering of positive charges on the surface of HA 13,14 . With gradually increased charges, disaggregation of HA first occurs as the positive charges repel each other, followed by the entry of water into the interior of the protein causing further structural changes of HA2 13 . In the HA2 subunit, one short and one long α-helical segment are connected by a loop (helix-loo...

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Section: Resultsmentioning

confidence: 99%

Exploration of binding and inhibition mechanism of a small molecule inhibitor of influenza virus H1N1 hemagglutinin by molecular dynamics simulation

Guan

Wang

Kuai

et al. 2017

Sci Rep

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show abstract

“…Both of these studies have indicated the S-helix to be parallel CC and modeled it as such. Some possible CC conformational changes could involve a loop-to-helix transition, as observed in influenza virus hemagglutinin HA2 [45], a shifting/flipping along the interface of the a-d knobs, as modeled for GCN4 [46], or rotation of the helices as evidenced in the HAMP structure [31]. In addition, a helix re-orientation from anti-parallel to parallel or vice versa can also not be ruled out.…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of the signaling helix coiled-coil domain of the β1 subunit of the soluble guanylyl cyclase

Beuve

Akker

2010

BMC Struct Biol

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BackgroundThe soluble guanylyl cyclase (sGC) is a heterodimeric enzyme that, upon activation by nitric oxide, stimulates the production of the second messenger cGMP. Each sGC subunit harbor four domains three of which are used for heterodimerization: H-NOXA/H-NOBA domain, coiled-coil domain (CC), and catalytic guanylyl cyclase domain. The CC domain has previously been postulated to be part of a larger CC family termed the signaling helix (S-helix) family. Homodimers of sGC have also been observed but are not functionally active yet are likely transient awaiting their intended heterodimeric partner.ResultsTo investigate the structure of the CC S-helix region, we crystallized and determined the structure of the CC domain of the sGCβ1 subunit comprising residues 348-409. The crystal structure was refined to 2.15 Å resolution.ConclusionsThe CC structure of sGCβ1 revealed a tetrameric arrangement comprised of a dimer of CC dimers. Each monomer is comprised of a long a-helix, a turn near residue P399, and a short second a-helix. The CC structure also offers insights as to how sGC homodimers are not as stable as (functionally) active heterodimers via a possible role for inter-helix salt-bridge formation. The structure also yielded insights into the residues involved in dimerization. In addition, the CC region is also known to harbor a number of congenital and man-made mutations in both membrane and soluble guanylyl cyclases and those function-affecting mutations have been mapped onto the CC structure. This mutant analysis indicated an importance for not only certain dimerization residue positions, but also an important role for other faces of the CC dimer which might perhaps interact with adjacent domains. Our results also extend beyond guanylyl cyclases as the CC structure is, to our knowledge, the first S-helix structure and serves as a model for all S-helix containing family members.

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“…In most influenza strains, this HisCat cluster is surrounded by additional cations; a His is highly conserved at position 185 and other cations often cluster around this region (Figure 5A). Indeed, this HisCat cluster lies at the HA1/HA1 interface and molecular dynamics simulations have predicted that as the pH decreases the HA1/HA1 interface is destabilized, opening a channel for water to solvate HA2 (Huang et al, 2002, 2009; Korte et al, 2007). …”

Section: Influenza a Virus Ha1/ha2mentioning

confidence: 99%

Role of Electrostatic Repulsion in Controlling pH-Dependent Conformational Changes of Viral Fusion Proteins

et al. 2013

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Viral fusion proteins undergo dramatic conformational transitions during membrane fusion. For viruses that enter through the endosome, these conformational rearrangements are typically pH sensitive. Here we provide a comprehensive review of the molecular interactions that govern pH-dependent rearrangements and introduce a novel paradigm for electrostatic residue pairings that regulate progress through the viral fusion coordinate. Analysis of structural data demonstrates a significant role for side chain protonation in triggering conformational change. To characterize this behavior we identify two distinct residue pairings, which we define as Histidine-Cation (HisCat) and Anion-Anion (AniAni) interactions. These side chain pairings destabilize a particular conformation via electrostatic repulsion through side chain protonation. Furthermore, two energetic control mechanisms, thermodynamic and kinetic, regulate these structural transitions. This review expands on the current literature by identification of these residue clusters, discussion of data demonstrating their function, and speculation of how these residue pairings contribute to the energetic controls.

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Energetics of the loop‐to‐helix transition leading to the coiled‐coil structure of influenza virus hemagglutinin HA2 subunits

Cited by 17 publications

References 70 publications

Exploration of binding and inhibition mechanism of a small molecule inhibitor of influenza virus H1N1 hemagglutinin by molecular dynamics simulation

Exploration of binding and inhibition mechanism of a small molecule inhibitor of influenza virus H1N1 hemagglutinin by molecular dynamics simulation

Crystal structure of the signaling helix coiled-coil domain of the β1 subunit of the soluble guanylyl cyclase

Role of Electrostatic Repulsion in Controlling pH-Dependent Conformational Changes of Viral Fusion Proteins

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