Structural Mimicry of CD4 by a Cross-reactive HIV-1 Neutralizing Antibody with CDR-H2 and H3 Containing Unique Motifs

Prabakaran, Ponraj; Gan, Jianhua; Wu, Yanze; Zhang, Meiyun; Dimitrov, Dimiter S.; Ji, Xinhua

doi:10.1016/j.jmb.2005.12.062

Cited by 20 publications

(40 citation statements)

References 76 publications

(88 reference statements)

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“…Perhaps most significant, however, is the implication that transition to the liganded conformation could be interrupted by ligands that bind to residues buried in the CD4-bound conformation but exposed in our unliganded model, including residues on α5 distal to α1, or outer-domain-facing residues on the N-terminal end of α1. There are several ligands known to bind near/at the CD4 site on gp120 that do not induce bridging sheet formation, such as the 12p1/HNG peptides (35) and monoclonal antibodies b12 (36,37), b13 (30), and m18 (38,39). Our unliganded model provides some basis upon which to speculate about how these and other noninducing ligands bind to gp120 and inhibit its function.…”

Section: Discussionmentioning

confidence: 94%

Large-scale conformational sampling of proteins using temperature-accelerated molecular dynamics

Abrams

Vanden‐Eijnden

2010

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

163

131

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We show how to apply the method of temperature-accelerated molecular dynamics (TAMD) in collective variables [Maragliano L, Vanden-Eijnden E (2006) Chem Phys Lett 426:168-175] to sample the conformational space of multidomain proteins in all-atom, explicitly solvated molecular dynamics simulations. The method allows the system to hyperthermally explore the free-energy surface in a set of collective variables computed at the physical temperature. As collective variables, we pick Cartesian coordinates of centers of contiguous subdomains. The method is applied to the GroEL subunit, a 55-kDa, three-domain protein, and HIV-1 gp120. For GroEL, the method induces in about 40 ns conformational changes that recapitulate the t → r 00 transition and are not observed in unaccelerated molecular dynamics: The apical domain is displaced by 30 Å, with a twist of 90°relative to the equatorial domain, and the root-mean-squared deviation relative to the r 00 conformer is reduced from 13 to 5 Å, representing fairly high predictive capability. For gp120, the method predicts both counterrotation of inner and outer domains and disruption of the so-called bridging sheet. In particular, TAMD on gp120 initially in the CD4-bound conformation visits conformations that deviate by 3.6 Å from the gp120 conformer in complex with antibody F105, again reflecting good predictive capability. TAMD generates plausible all-atom models of the so-far structurally uncharacterized unliganded conformation of HIV-1 gp120, which may prove useful in the development of inhibitors and immunogens. The fictitious temperature employed also gives a rough estimate of 10 kcal∕mol for the free-energy barrier between conformers in both cases.biophysical simulation | domain motion | free energy | collective variables S ince Koshland's introduction of the concept of "induced fit" (1), it is well accepted that conformational changes upon ligand binding underlie a substantial fraction of protein functionality (2, 3). Crystal structures of hundreds of proteins in both apo and liganded states often display evidence for motion of domains relative to one another over length scales characteristic of the domains themselves (4). Crystallographic conformers of the same protein, however, cannot provide much insight into the detailed mechanism of conformational change, especially if more than one hinge or other flexible element is involved. Even worse, there are many multidomain proteins for which only a single crystallographic conformer exists despite functional requirements for multiple conformers. On top of obscuring the structural biology of many multidomain proteins, often a single crystallographic conformer is too narrow a basis upon which to design molecules that act as allosteric effectors: agents that stabilize either active or inhibitory conformations by binding to sites other than those used by the primary ligands. It has therefore become attractive to probe the details of protein conformational dynamics using simulation methods, such as molecular dynamics (MD) and relat...

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Section: Discussionmentioning

confidence: 94%

Large-scale conformational sampling of proteins using temperature-accelerated molecular dynamics

Abrams

Vanden‐Eijnden

2010

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

163

131

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“…A more recently described broadly neutralizing anti-CD4 binding site antibody m18, which was identified using sequential antigen panning [367], has an extended phenylalanine in a -hairpin structure that mimics the CD4 phenylalanine 43 and Ig CDR2-like C'C" region of CD4's first domain (Fig. 1C) [269]. Thus, these antibodies structurally mimic CD4.…”

Section: Targeting the Cd4 Binding Sitementioning

confidence: 98%

“…In addition to cross competition analyses with CD4 and anti-CD4 binding site antibodies, mutagenesis studies and antibody-Env docking analyses have been done to further define these epitopes [251,269,293]. Curiously b12 maps and docks quite well to the CD4 liganded gp120 core structure and not to the unliganded core [41,293].…”

Section: Targeting the Cd4 Binding Sitementioning

confidence: 99%

Designing Immunogens to Elicit Broadly Neutralizing Antibodies to the HIV-1 Envelope Glycoprotein

Lin

Nara²

2007

CHR

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To date HIV-1 vaccines have not been able to elicit potent, long lasting, and broadly neutralizing antibodies to the virus. Our knowledge of HIV envelope glycoprotein (Env) structure/function and the existence of a handful of broadly neutralizing antibodies is guiding rational immunogen design. We review here the potential targets on the HIV Env (the glycan shield, the CD4 binding site, the coreceptor binding site, Env fusion intermediates, and the membrane proximal region) and their associated rational immunogen design strategies. Moreover, we discuss immune dampening and immune refocusing strategies designed to counter immunodominant, decoy responses generated by the virus. In this regard, an immunogen design strategy of "in vitro de-evolution" is presented, which begins to distill the HIV Env to its most critical, core functional domains. While we are beginning to have some understanding as to where we would like out immune system to go, we find that our immune repertoire may actually have limits that preclude successful completion of the task at hand. The repertoire limits appear to be a byproduct of autoantibody tolerance mechanisms and the complex structural requirements for effective, potent broadly neutralizing antibodies. Nevertheless, the hope is that through novel insights and creative solutions that we will be able to design immunogens capable of eliciting broadly neutralizing antibodies to the HIV envelope glycoprotein.

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“…Among them we find PG9 and PG16 (which neutralize 70 to 80% of circulating HIV-1 isolates), CH01 to CH04 (which neutralize 40 to 50% of isolates), and PGT141 to -145 (which neutralize 40 to 80%) (6,145,146). The third variable loop (V3) of HIV-1 gp120 is comprised of 35 amino acids (aa), which are arranged in a disulfide loop involving two cysteines and play an important role in coreceptor selection (CCR5 or CXCR4), and is a target site for NAbs (105,157). Indeed, removal of a single Nlinked glycosylation site in the V3 loop (position 301) increases the sensitivity of primary isolates to neutralization.…”

Section: Hiv-1 Envelope Glycoproteinmentioning

confidence: 99%

“…All of these contain long H3s regions that play a major role in their mechanism of binding. The H3s regions of X5, m6, and m9 appear to be very flexible and highly potent at neutralizing HIV (88,105,150,158). Recent works from Corti et al have described new and potent bNAbs HGN194 and HJ16, directed against gp120 (20) ( Table 1).…”

Section: Gp120 Immunogenicitymentioning

confidence: 99%

Role of Human Immunodeficiency Virus Type 1 Envelope Structure in the Induction of Broadly Neutralizing Antibodies

Benjelloun

Lawrence

Verrier

et al. 2012

J Virol

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c Very soon after the discovery of neutralizing antibodies (NAbs) toward human immunodeficiency virus type 1 (HIV-1) infection, it became apparent that characterization of these NAbs would be an important step in finding a cure for or a vaccine to eradicate HIV-1. Since the initial description of broadly cross-clade NAbs naturally produced in HIV-1 patients, numerous studies have described new viral targets for these antibodies. More recently, studies concerning new groups of patients able to control their viremia, such as long-term nonprogressors (LTNPs) or elite controllers, have described the generation of numerous envelope-targeted NAbs. Recent studies have marked a new stage in research on NAbs with the description of antibodies obtained from a worldwide screening of HIV-positive patients. These studies have permitted the discovery of NAb families with great potential for both neutralization and neutralization breadth, such as PG, PGT, CH, and highly active agonistic anti-CD4 binding site antibodies (HAADs), of which VRC01 and its variants are members. These antibodies are able to neutralize more than 80% of circulating strains without any autoreactivity and can be rapidly integrated into clinical trials in order to test their protective potential. In this review, we will focus on new insights into HIV-1 envelope structure and their implications for the generation of potent NAbs.

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Structural Mimicry of CD4 by a Cross-reactive HIV-1 Neutralizing Antibody with CDR-H2 and H3 Containing Unique Motifs

Cited by 20 publications

References 76 publications

Large-scale conformational sampling of proteins using temperature-accelerated molecular dynamics

Large-scale conformational sampling of proteins using temperature-accelerated molecular dynamics

Designing Immunogens to Elicit Broadly Neutralizing Antibodies to the HIV-1 Envelope Glycoprotein

Role of Human Immunodeficiency Virus Type 1 Envelope Structure in the Induction of Broadly Neutralizing Antibodies

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