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      Biophysical and Structural Studies on the Capsid Protein of the Human Immunodeficiency Virus Type 1: A New Drug Target?

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          Abstract

          AIDS affects 30 million people worldwide and is one of the deadliest epidemics in human history. It is caused by a retrovirus, HIV, whose mature capsid (enclosing the RNA with other proteins) is formed by the assembly of several hundred copies of a protein, CA*. The C-terminal domain of such protein, CAC, is a driving force in virus assembly and the connections in the mature capsid lattice indicate that CAC joins through homodimerization of the CA hexamers. In the first part of this work, I shall review the biophysical studies carried out with the dimeric wild-type CAC protein and a mutant monomeric variant. The results open new venues for the development of drugs able to interact either with the dimeric species, hampering its assembly, or with the monomeric species, obstructing its folding. In the second part of this review, I shall describe the structures of complexes of CAC with small molecules able to weaken its dimerization. Furthermore, interactions with other proteins and lipids are also described. The whole set of results suggests that much of the surface of CAC does not accommodate binding per se, but rather binding sites in the protein are predefined, i.e., there are “hot” spots for binding in CAC (whatever be the molecule to bind). These “hot” residues involve most of the dimerization interface (an α-helix) of the CAC wild-type protein, but also polypeptide patches at the other helices.

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          Most cited references34

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          Recognition of transmembrane helices by the endoplasmic reticulum translocon.

          Membrane proteins depend on complex translocation machineries for insertion into target membranes. Although it has long been known that an abundance of nonpolar residues in transmembrane helices is the principal criterion for membrane insertion, the specific sequence-coding for transmembrane helices has not been identified. By challenging the endoplasmic reticulum Sec61 translocon with an extensive set of designed polypeptide segments, we have determined the basic features of this code, including a 'biological' hydrophobicity scale. We find that membrane insertion depends strongly on the position of polar residues within transmembrane segments, adding a new dimension to the problem of predicting transmembrane helices from amino acid sequences. Our results indicate that direct protein-lipid interactions are critical during translocon-mediated membrane insertion.
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            Experimentally determined hydrophobicity scale for proteins at membrane interfaces

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              Crystal structure of human cyclophilin A bound to the amino-terminal domain of HIV-1 capsid.

              The HIV-1 capsid protein forms the conical core structure at the center of the mature virion. Capsid also binds the human peptidyl prolyl isomerase, cyclophilin A, thereby packaging the enzyme into the virion. Cyclophilin A subsequently performs an essential function in HIV-1 replication, possibly helping to disassemble the capsid core upon infection. We report the 2.36 A crystal structure of the N-terminal domain of HIV-1 capsid (residues 1-151) in complex with human cyclophilin A. A single exposed capsid loop (residues 85-93) binds in the enzyme's active site, and Pro-90 adopts an unprecedented trans conformation. The structure suggests how cyclophilin A can act as a sequence-specific binding protein and a nonspecific prolyl isomerase. In the crystal lattice, capsid molecules assemble into continuous planar strips. Side by side association of these strips may allow capsid to form the surface of the viral core. Cyclophilin A could then function by weakening the association between capsid strips, thereby promoting disassembly of the viral core.
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                Author and article information

                Journal
                ScientificWorldJournal
                ScientificWorldJournal
                TSWJ
                The Scientific World Journal
                TheScientificWorldJOURNAL
                2356-6140
                1537-744X
                2009
                29 May 2009
                : 9
                : 404-419
                Affiliations
                1 Instituto de Biología Molecular y Celular, Universidad Miguel Hernáez, 03202 Elche (Alicante), Spain
                2 Biocomputation and Complex Systems Physics Institute, 50009 Zaragoza, Spain
                Author notes
                *José L. Neira: jlneira@ 123456umh.es

                Academic Editor: Nuno C. Santos

                Article
                215946
                10.1100/tsw.2009.52
                5823109
                19484162
                de7f9b0c-b506-4aa8-9651-9fd4b74d7860
                Copyright © 2009 Jose L Neira.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 12 December 2008
                : 13 May 2009
                : 18 May 2009
                Categories
                Review Article

                Uncategorized
                protein structure,binding,cac protein,lipids,protein-peptide interactions,protein-protein interactions,organic molecules

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