Model for the structure of the HIV gp41 ectodomain: insight into the intermolecular interactions of the gp41 loop

Abstract

In human immunodeficiency virus (HIV) the viral envelope proteins gp41 and gp120 form a non-covalent complex, which is a potential target for AIDS therapies. In addition gp41 plays a possible role in HIV infection of B cells via the complement system. In an effort to better understand the molecular interactions of gp41, the structure of the HIV gp41 ectodomain has been modeled using the NMR restraints of the simian immunodeficiency virus (SIV) gp41 ectodomain (M. Caffrey, M. Cai, J. Kaufman, S.J. Stahl, P.T. Wingfield, A.M. Gronenborn, G.M. Clore, Solution structure of the 44 kDa ectodomain of SIV gp41, EMBO J. 17 (1998) 4572--4584). The resulting model presents the first structural information for the HIV gp41 loop, which has been implicated to play a direct role in binding to gp120 and C1q of the complement system.

Solution structure of the HIV gp120 C5 Domain

“…Furthermore, antibody accessibility studies have suggested that the amino terminal region of the gp120 C5 domain (residues 489-500) is not exposed in the gp120/gp41 complex but exposed in the monomeric form when gp120 dissociates from gp41 [36], consistent with the notion that the hydrophobic ÔelbowÕ of C5 (Fig. 5B) interacts with the hydrophobic loop region of gp41 [18,33]. In total, the resulting model is consistent with a large number of biochemical and structural studies.…”

“…Moreover, substitution of I491, P493, G495, A497, P498, T499 or A501 by cysteines resulted in intermolecular crosslinks to non-native cysteines introduced into the gp41 loop region [10]. Together the mutagenesis, structural studies, and fluorescence titration experiments [7,18,29,33] (and the present work) provide compelling evidence that the hydrophobic loop of gp41 interacts with the hydrophobic turn region of C5.…”

“…7, we present a model of the gp41 and gp120 components, which were determined by The exposed tryptophans found in the gp41 loop are labeled. The unlabeled tryptophans, which include W60, W117 and W120, are found in the protein interior and not exposed to solvent [18,33].…”

“…Disruption of this binding is expected to inhibit HIV infection and thus the C5 domain is an attractive target for structure-based drug therapies. The HIV gp41 ectodomain is shown in blue and is a taken from the model structure [33], which is based on the NMR structure of the SIV gp41 ectodomain [18]. The gp120 C5 structure is shown in red and is taken from the present work.…”

Viral surface glycoproteins, gp120 and gp41, as potential drug targets against HIV-1: Brief overview one quarter of a century past the approval of zidovudine, the first anti-retroviral drug

“…Concerning the structural information for the loop, FP and TM domains of the viral protein, Caffrey et al presented a model for the structure of the HIV-1 gp41 loop [132], which is based on the solution structure of the SIV gp41 ectodomain [133]. The resulting model presents the first structural information for the HIV gp41 loop, which has been implicated to play a direct role in binding to gp120 and C1q of the complement system.…”