August 31, 2011
This demonstration is an update from an advisory committee demonstration presented in November 2009.
Data files data.zip.
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|  Cytoscape network of HIV strains showing that PDB structures cover very little of the diversity of HIV strains (all structures are clade B predominant in United States and Europe). This limits understanding of broadly neutralizing antibodies. |
| Intro to HIV antibodies.
Video, 5 minutes. | Antibody binding positions.
Video, 8 minutes. blast_1gc1_session.py binding_positions_session.py | Conserved residues.
Video, 13 minutes. conservation_session.py | Structure diversity. Scooter will provide Cytoscape video demo. |
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| gp120 homology model.
Video, 9 minutes. homology_session.py | gp120 glycosylation.
Video, 8 minutes. glycosylation_session.py | SAXS for assessing V1/V2 loop position. No video. Kruger SAXS data isn't close to matching a monomer of gp120 size so something is wrong, making this demo less compelling. | SIV electron microscopy.
Video, 7 minutes. siv_virion_session.py | Trimeric EM model.
No video yet. fit_trimer_session.py |
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| Animating trimer conformational change.
Movie. |
These are notes for a Chimera tool demonstration centered on structures of recently discovered broadly neutralizing antibodies that target the gp120 protein in HIV glycoprotein spikes, initially discovered in 2009.
Since the 2009 publication of PG9 and PG16 broadly neutralizing antibodies (bNAb), 17 additional bNAbs some up to 10 times tighter binders have been isolated from 4 patients infected with HIV that show strong suppression of the virus, work published in Nature, August 2011. The 2009 antibodies were isolated from a single African HIV patient.
There have been 5 new publications on HIV bNAbs by the same authors since the 2009 discovery.
Results of search of Walker LM HIV vaccine at PubMed:
1. Broad neutralization coverage of HIV by multiple highly potent antibodies. Walker LM, Huber M, Doores KJ, Falkowska E, Pejchal R, Julien JP, Wang SK, Ramos A, Chan-Hui PY, Moyle M, Mitcham JL, Hammond PW, Olsen OA, Phung P, Fling S, Wong CH, Phogat S, Wrin T, Simek MD, Principal Investigators PG, Koff WC, Wilson IA, Burton DR, Poignard P. Nature. 2011 Aug 17. doi: 10.1038/nature10373. [Epub ahead of print] PMID: 21849977 2. Mechanism of Neutralization by the Broadly Neutralizing HIV-1 Monoclonal Antibody VRC01. Li Y, O'Dell S, Walker LM, Wu X, Guenaga J, Feng Y, Schmidt SD, McKee K, Louder MK, Ledgerwood JE, Graham BS, Haynes BF, Burton DR, Wyatt RT, Mascola JR. J Virol. 2011 Sep;85(17):8954-67. Epub 2011 Jun 29. PMID: 21715490 3. A limited number of antibody specificities mediate broad and potent serum neutralization in selected HIV-1 infected individuals. Walker LM, Simek MD, Priddy F, Gach JS, Wagner D, Zwick MB, Phogat SK, Poignard P, Burton DR. PLoS Pathog. 2010 Aug 5;6(8). pii: e1001028. PMID: 20700449 4. Structure and function of broadly reactive antibody PG16 reveal an H3 subdomain that mediates potent neutralization of HIV-1. Pejchal R, Walker LM, Stanfield RL, Phogat SK, Koff WC, Poignard P, Burton DR, Wilson IA. Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11483-8. Epub 2010 Jun 2. PMID: 20534513 5. Rational antibody-based HIV-1 vaccine design: current approaches and future directions. Walker LM, Burton DR. Curr Opin Immunol. 2010 Jun;22(3):358-66. Epub 2010 Mar 17. Review. PMID: 20299194 6. Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Walker LM, Phogat SK, Chan-Hui PY, Wagner D, Phung P, Goss JL, Wrin T, Simek MD, Fling S, Mitcham JL, Lehrman JK, Priddy FH, Olsen OA, Frey SM, Hammond PW; Protocol G Principal Investigators, Kaminsky S, Zamb T, Moyle M, Koff WC, Poignard P, Burton DR. Science. 2009 Oct 9;326(5950):285-9. Epub 2009 Sep 3. PMID: 19729618
No structures of the PG9 and PG16 broadly neutralizing antibodies bound to gp120 have been determined so far, although structures of these antibodies in isolation were published in 2010, PDB 3mug and 3muh.
Structures of other broadly neutralizing HIV antibodies bound to gp120 have been found in 2010 and 2011. Search pdb for gp120 broadly neutralizing:
3SE8 Crystal structure of broadly and potently neutralizing antibody VRC03 in complex with HIV-1 gp120. August 10, 2011 3SE9 Crystal structure of broadly and potently neutralizing antibody VRC-PG04 in complex with HIV-1 gp120 August 10, 2011 3NGB Crystal structure of broadly and potently neutralizing antibody VRC01 in complex with HIV-1 gp120 July 7, 2010
The following PDBs show a range of antibody binding locations on gp120: 1gc1, 2ny7, 3lqa, 3se8. Load these from the BLAST results.
It is necessary to load 1gc1 even though it is already loaded because the original copy will not align with the BLAST loaded models.
Color all gp120 chains gray and hide CD4 chains with commands
color gray :.G ~ribbon :.C