Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Novel Bent Conformation of CD4 Induced by HIV-1 Inhibitor Indirectly Prevents Productive Viral Attachment.
Journal, issue, pages	J Mol Biol, Vol. 434, Issue 2, Page 167395, Year 2022
Publish date	Jan 30, 2022
Authors	David Wensel / Shawn Williams / David P Dixon / Paris Ward / Patti McCormick / Nestor Concha / Eugene Stewart / Xuan Hong / Charles Mazzucco / Shreya Pal / Bo Ding / Christoph Fellinger / Mark Krystal /
PubMed Abstract	GSK3732394 is a multi-specific biologic inhibitor of HIV entry currently under clinical evaluation. A key component of this molecule is an adnectin (6940_B01) that binds to CD4 and inhibits ...GSK3732394 is a multi-specific biologic inhibitor of HIV entry currently under clinical evaluation. A key component of this molecule is an adnectin (6940_B01) that binds to CD4 and inhibits downstream actions of gp160. Studies were performed to determine the binding site of the adnectin on CD4 and to understand the mechanism of inhibition. Using hydrogen-deuterium exchange with mass spectrometry (HDX), CD4 peptides showed differential rates of deuteration (either enhanced or slowed) in the presence of the adnectin that mapped predominantly to the interface of domains 2 and 3 (D2-D3). In addition, an X-ray crystal structure of an ibalizumab Fab/CD4(D1-D4)/adnectin complex revealed an extensive interface between the adnectin and residues on CD4 domains D2-D4 that stabilize a novel T-shaped CD4 conformation. A cryo-EM map of the gp140/CD4/GSK3732394 complex clearly shows the bent conformation for CD4 while bound to gp140. Mutagenic analyses on CD4 confirmed that amino acid F202 forms a key interaction with the adnectin. In addition, amino acid L151 was shown to be a critical indirect determinant of the specificity for binding to the human CD4 protein over related primate CD4 molecules, as it appears to modulate CD4's flexibility to adopt the adnectin-bound conformation. The significant conformational change of CD4 upon adnectin binding brings the D1 domain of CD4 in proximity to the host cell membrane surface, thereby re-orienting the gp120 binding site in a direction that is inaccessible to incoming virus due to a steric clash between gp160 trimers on the virus surface and the target cell membrane.
External links	J Mol Biol / PubMed:34896364
Methods	EM (single particle) / X-ray diffraction
Resolution	3.65 - 8.7 Å
Structure data	25581 7t0o EMDB-25581, PDB-7t0o: cryoEM reconstruction of the HIV gp140 in complex with the extracellular domains of CD4 and the adnectin domain of Combinectin. The gp140 and CD4 coordinates from entry 6EDU were rigid body fitted to the EM map along withe the crystal structure of CD4+adnectin Method: EM (single particle) / Resolution: 8.7 Å PDB-7t0r: Crystal structure of the anti-CD4 adnectin 6940_B01 as a complex with the extracellular domains of CD4 and ibalizumab fAb Method: X-RAY DIFFRACTION / Resolution: 3.65 Å
Chemicals	ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose ChemComp-SO4: SULFATE ION
Source	hiv-1 06tg.ht008 (virus) homo sapiens (human) mus musculus (house mouse) synthetic construct (others)
Keywords	ANTIVIRAL PROTEIN / Inhibitor / HIV gp140 / CD4 / adnectin / ibalizumab / HIV Env / combinectin