Dual conformations for the HIV-1 gp120 V3 loop in complexes with different neutralizing Fabs

Stanfield, RL; Cabezas, Edelmira; Satterthwait, A.C; Stura, E.A.; Profy, A.T.; Ia, Wilson

doi:10.1016/s0969-2126(99)80020-3

Cited by 130 publications

(128 citation statements)

References 81 publications

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“…The flexibility conferred by this highly conserved glycine residue meets the requirements for permitting the spatial and temporal relationships of the C-terminal α-helix and the N-terminal loop. This finding is consistent with the generally accepted role of glycine in providing the freedom necessary for the regulation of both folding and function of a protein (22)(23)(24)(25)(26)(27)(28). In addition, it has been found experimentally that Gly 436 has a functional role in the entry process of the virus (6).…”

Section: Discussionsupporting

confidence: 89%

Discrete conformations of epitope II on the hepatitis C virus E2 protein for antibody-mediated neutralization and nonneutralization

Deng

Virata-Theimer

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The X-ray crystal structure of epitope II on the E2 protein of hepatitis C virus, in complex with nonneutralizing antibody mAb#12, has been solved at 2.90-Å resolution. The spatial arrangement of the essential components of epitope II (ie, the C-terminal α-helix and the N-terminal loop) was found to deviate significantly from that observed in those corresponding complexes with neutralizing antibodies. The distinct conformations are mediated largely by the flexibility of a highly conserved glycine residue that connects these components. Thus, it is the particular tertiary structure of epitope II, which is presented in a spatial and temporal manner, that determines the specificity of antibody recognition and, consequently, the outcome of neutralization or nonneutralization.H epatitis C is a major public health problem worldwide. More than 170 million people are infected by the hepatitis C virus (HCV) (1). Approximately 70% of infected people fail to clear the virus during the acute phase of the disease and become chronic carriers (2). Liver cirrhosis, which develops in about 10-20% of chronically infected patients, is linked with a high risk for hepatocellular carcinoma in later life (2, 3). To date, there is neither an effective immune globulin for prophylaxis nor a vaccine for the prevention of hepatitis C. The development of a safe and effective HCV vaccine remains a top priority for the global control of HCV infections.The HCV envelope glycoprotein E2 has long been considered an important immunogenic target in efforts to develop an HCV vaccine candidate. This consideration is largely based on the role of the E2 protein in facilitating the entry of HCV into hepatocytes via interaction with the host entry factors (4-10). Recently, the crystal structure of the E2 core, in complex with a neutralizing antibody, was solved (11). The E2 core study described the interface crucial for host entry factor CD81-mediated entry, thus providing a site of vulnerability that can be exploited in immunogen design. The crystal structure also revealed that nearly 62% of the E2 core amino acid residues are either disordered or in loop structures, the overall effect of which indicates a striking flexibility in the E2 protein structures. Whether the intrinsic structural heterogeneity of the E2 protein is linked to the viral entry process or not is currently unknown.Epitope II resides on the E2 protein between residues 427 and 446, a location that places it in the vicinity of the described E2-CD81 interface in the flexible area of the E2 protein (11-13). Paradoxically, different antibodies are able to bind to a similar set of residues on epitope II; however, their interactions with these residues can lead to either HCV neutralization or nonneutralization, as defined in an in vitro HCV cell culture system (12, 13). In addition, some epitope II-specific nonneutralizing antibodies were shown to interfere with the neutralization by antibodies at epitope I, another epitope on the E2 protein between residues 412 and 426 (12). Furthermore, de...

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Section: Discussionsupporting

confidence: 89%

Discrete conformations of epitope II on the hepatitis C virus E2 protein for antibody-mediated neutralization and nonneutralization

Deng

Virata-Theimer

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Crystal structure of activated Bax epitope FW Peyerl et al disallowed region (Table 1), which is a highly conserved g turn in most antibody structures. 22 The electron density omit map clearly defined the orientation and conformation of the Bax peptide in the 6A7 binding site (Figure 1c). The only peptide side chain residue with poorly defined electron density was solvent-exposed Q18.…”

Section: Resultsmentioning

confidence: 93%

Elucidation of some Bax conformational changes through crystallization of an antibody–peptide complex

et al. 2006

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The Bcl-2 family member Bax plays a critical role in apoptosis. In healthy resting cells, Bax resides in the cytoplasm and loosely attached to the mitochondrial membrane. Apoptotic stimuli induce Bax activation, which is characterized by translocation and multimerization on the mitochondrial membrane surface resulting in exposure of an amino terminal epitope recognized by the monoclonal antibody 6A7. To understand the structural changes that occur during Bax activation, we determined the crystal structure of a Bax peptide bound to the 6A7 Fab fragment to a resolution of 2.3 Å . The structure reveals the conformation of the 6A7 peptide epitope on Bax in the activated form and elucidates the extensive structural changes that Bax must undergo during the conversion from its native to its activated conformation.

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“…Additionally, the structures of several neutralizing antibodies complexed with their V3 loop epitopes revealed that the V3 loop exists in at least two quite different conformation (48). This suggests that the V3 loop may adopt different structures, adding yet another layer of difficulty to its recognition by the immune system.…”

Section: Discussionmentioning

confidence: 99%

Oligomeric Modeling and Electrostatic Analysis of the gp120 Envelope Glycoprotein of Human Immunodeficiency Virus

Kwong

Wyatt

Sattentau

et al. 2000

J Virol

247

196

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The human immunodeficiency virus envelope glycoproteins, gp120 and gp41, function in cell entry by binding to CD4 and a chemokine receptor on the cell surface and orchestrating the direct fusion of the viral and target cell membranes. On the virion surface, three gp120 molecules associate noncovalently with the ectodomain of the gp41 trimer to form the envelope oligomer. Although an atomic-level structure of a monomeric gp120 core has been determined, the structure of the oligomer is unknown. Here, the orientation of gp120 in the oligomer is modeled by using quantifiable criteria of carbohydrate exposure, occlusion of conserved residues, and steric considerations with regard to the binding of the neutralizing antibody 17b. Applying similar modeling techniques to influenza virus hemagglutinin suggests a rotational accuracy for the oriented gp120 of better than 10°. The model shows that CD4 binds obliquely, such that multiple CD4 molecules bound to the same oligomer have their membrane-spanning portions separated by at least 190 Å. The chemokine receptor, in contrast, binds to a sterically restricted surface close to the trimer axis. Electrostatic analyses reveal a basic region which faces away from the virus, toward the target cell membrane, and is conserved on core gp120. The electrostatic potentials of this region are strongly influenced by the overall charge, but not the precise structure, of the third variable (V3) loop. This dependence on charge and not structure may make electrostatic interactions between this basic region and the cell difficult to target therapeutically and may also provide a means of viral escape from immune system surveillance.The human immunodeficiency viruses (types 1 [HIV-1] and 2 [HIV-2]) and related simian viruses (SIVs) cause the depletion and functional dysregulation of CD4 ϩ lymphocytes, resulting in the development of AIDS. The HIV envelope contains two glycoproteins: gp120, the exterior receptor-binding component, and its noncovalently interacting partner, gp41, the transmembrane envelope glycoprotein. Only half of gp41 is exposed in the ectodomain; the other half, separated by a transmembrane region, is thought to anchor the envelope complex to the underlying matrix. New infections are initiated by interaction of gp120 with the N-terminal membrane-distal domain of CD4, a glycoprotein on the surface of specific cells of the immune system (12, 29). A second interaction of gp120, with a member of the chemokine receptor family, primarily CCR5 or CXCR4, is believed to trigger conformational changes in gp41, which ultimately mediates virus-cell membrane fusion (20,38).HIV receptor binding takes place in the context of an oligomeric viral spike. Atomic-level structures have been determined for many of the component molecules: the entire extracellular portion of CD4 (60), the complex of monomeric core gp120 (a truncated version of gp120 with deletions of the gp41-interactive region at the N and C termini as well as of the variable V1/V2 and V3 loops) with the two N-terminal domains of...

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Dual conformations for the HIV-1 gp120 V3 loop in complexes with different neutralizing Fabs

Abstract: The V3 loop can adopt at least two different conformations for the highly conserved Gly-Pro-Gly-Arg sequence at the tip of the loop. Thus, the HIV-1 V3 loop has some inherent conformational flexibility that may relate to its biological function.

Cited by 130 publications

References 81 publications

Discrete conformations of epitope II on the hepatitis C virus E2 protein for antibody-mediated neutralization and nonneutralization

Discrete conformations of epitope II on the hepatitis C virus E2 protein for antibody-mediated neutralization and nonneutralization

Elucidation of some Bax conformational changes through crystallization of an antibody–peptide complex

Oligomeric Modeling and Electrostatic Analysis of the gp120 Envelope Glycoprotein of Human Immunodeficiency Virus

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