{{STRUCTURE_2nmz| PDB=2nmz | SCENE= HIV-1_protease/2nmz/3 }}

== Introduction ==

HIV is a notoriously lethal retrovirus that is known to cause AIDS<ref>PMID:3072672</ref>. There currently is no cure or vaccine, but, scientists have discovered treatments that can slow progression of the HIV virus, thanks in large part to our understanding of the structure of [[HIV-1 protease]] (EC.3.4.23.16), seen here on the right in complex with a potent drug used for slowing the progression of HIV, <scene name='HIV-1_protease/2nmz_saquinavir/2'>Saquinavir</scene> (PDB entry [[2nmz]]).

HIV-1 protease is a protein made by the HIV virus that is crucial to the virus's infectious capacity. The virus makes certain proteins that need to be cleaved, or cut, in order to transform into mature, fully-functional proteins that can allow the virus to infect new cells. HIV-1 protease is responsible for cleaving these nascent proteins into their mature form at a rate 10^10 faster than that of the uncatalyzed reaction in water<ref name="rasmol3">PMID:16784222</ref>.

[[Image:HIV_protease_active_site.jpg|350px|HIV protease active site]]

== Structure ==

Looking at the structure of HIV-1 protease, we see that the protein is composed of <scene name='HIV-1_protease/2nmz_symmetric/2'>two symmetrically related subunits</scene> shown here in [[cartoon backbone representation]] to highlight [[secondary structure]]. Each subunit of the homodimer consists of a small 99 amino acid chain. The subunits come together in such as way as to <scene name='HIV-1_protease/2nmz_tunnel/1'>form a tunnel where they meet</scene>, shown here in [[spacefilling representation]] to showcase the physical surface of the protein. The protein to be cleaved sits in this tunnel. In the middle of the tunnel is the <scene name='HIV-1_protease/2nmz_triads/1'>active site</scene> of the protease: <scene name='HIV-1_protease/2nmz_triadslabeled/2'>two Asp-Thr-Gly catalytic triads</scene> (residue numbers 25, 26, and 27 on one chain and 25', 26', and 27' on the second). <scene name='HIV-1_protease/2nmz_aspslabeled/1'>The two Asp's</scene> act as the main catalytic residues in the active site and use a water molecule to help break the protein chain that binds in the tunnel. You may be wondering how a protein to be cleaved makes its way into the active-site tunnel to begin with -- after all, the tunnel does not seem so accessible. The key is the two flexible β-hairpin flaps on the top of the tunnel that can <scene name='HIV-1_protease/Hiv1_protease_morph/4'>move</scene> (large scene, takes a while to load) to allow proteins to enter the tunnel. A <scene name='HIV-1_protease/Hiv1_p_morph_sp/2'>spacefill view of the flexible flaps</scene> is also illuminating, as the change in the accessibility of the tunnel becomes more obvious. This movement of the flexible flaps is simulated by morphing between two crystal structures, the first being the native HIV-1 protease structure with no inhibitor bound (PDB entry [[1hhp]]) and the second being the HIV-1 protease complexed with Saquinavir. As you can imagine, if an inhibitor is bound to the active site of HIV protease, other polyprotein precursors for HIV cannot bind, therefore, inhibiting the productions of mature proteins and ultimately the ability for these proteins to infect other cells.

==Mechanism==

HIV protease is classified as an aspartic protease. Evidence for this classification is listed below:

1) The Asp-Thr-Gly in the active site of HIV protease is highly conserved in aspartic protease enzymes<ref>PMID:3045565</ref>.

2) Mutational analysis studies have shown that mutation of one of these essential Asp-25 groups to Asn, Thr, or Ala resulted in complete loss of proteolytic activity<ref>PMID:3290901</ref><ref name="rasmol">PMID:2644259</ref><ref name="rasmol1">PMID:12097607</ref><ref>PMID:2450209</ref>.

3) HIV protease is inhibited in vitro by pepstatin, a known inhibitor of aspartic proteases<ref name="rasmol" /><ref name="rasmol1" /><ref>PMID:3049075</ref>.

4) The 3-dimensional Homodimeric structure is characteristic of aspartic proteases<ref>PMID:2645523</ref><ref>PMID:2686029</ref><ref>PMID:2682266</ref>.

There has been much debate over the protonation state of Asp 25 and Asp 25'. Time-dependent kinetics of HIV protease with 1,2-epoxy-3-(4-nitrophenoxy)propane, a known aspartic protease inhibitor, from Meek ''et al.'' suggest that only one Asp is protonated in the active site of the enzyme<ref>PMID:2648384</ref>. However, theoretical calculations by Piana ''et al.'' indicated the presence of a low-barrier hydrogen bond (LBHB) between the two negatively charged oxygens of Asp 25 and Asp 25'<ref>PMID:10737924</ref>. Das ''et al.'' later determined that the inner oxygen atoms of the aspartates were 2.3 Â apart, supporting the LBHB prediction<ref>PMID:17116869</ref>. Recent computer simulation studies using HIV protease have lead to the conclusion that the LBHB is more important for enhancing the rate of enzymatic reactions rather than the dynamic effects <ref name="rasmol3" />. Northrop proposed a mechanism for aspartic proteases with the inclusion of a LBHB between the two inner carboxylate oxygen atoms of aspartate<ref>PMID:11601963</ref>.
==Proposed mechanism by Northrop==
[[Image:HIV-1_Protease_mechanism.jpg]]

== Evolutionary History ==

A phylogenic tree showing the relationships between selected retroviral proteases.

==Inhibitors==

Saquinavir was the the first protease inhibitor approved by the FDA for the treatment of HIV. It inhibits HIV-1 protease by <scene name='HIV-1_protease/2nmz_saquinavir_spacefill/1'>binding tightly to the active site tunnel</scene>, thus preventing the protease from cleaving any protein chains.

Other drugs used to treat patients infected with the HIV virus include Indinavir (PDB entry [[1hsg]]), Ritonavir (PDB entry [[1hxw]]), and Nelfinavir (PDB entry [[1ohr]]).

{{Clear}}

==References==
<references />

*Atomic resolution crystal structures of HIV-1 protease and mutants V82A and I84V with saquinavir., Tie Y, Kovalevsky AY, Boross P, Wang YF, Ghosh AK, Tozser J, Harrison RW, Weber IT, Proteins. 2007 Apr 1;67(1):232-42. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17243183 17243183]
*The three-dimensional structure of the aspartyl protease from the HIV-1 isolate BRU., Spinelli S, Liu QZ, Alzari PM, Hirel PH, Poljak RJ, Biochimie. 1991 Nov;73(11):1391-6. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/1799632 1799632]

==Links==
* HIV-1 Protease featured in [[User:David S. Goodsell | David S. Goodsell's]] [http://mgl.scripps.edu/people/goodsell/pdb/pdb6/pdb6_1.html Molecule of the Month]
* HIV-1 Protease in [http://en.wikipedia.org/wiki/HIV-1_protease Wikipedia]

User:Nicole Maille/Sandbox 1

2010-05-02T02:50:47Z

Nicole Maille:

User:Nicole Maille/Sandbox 1

2010-05-02T02:36:19Z

Nicole Maille:

File:HIV protease active site.jpg

2010-05-02T02:20:29Z

Nicole Maille: uploaded a new version of "Image:HIV protease active site.jpg": A schematic representation of substrate bound to the active site of HIV protease. The active site contains eight "subsites," S4, S3, S2, S1, S1', S2', S3' and S4' that are interacting wit

== Summary ==
A schematic representation of substrate bound to the active site of HIV protease. The active site contains eight "subsites," S4, S3, S2, S1, S1', S2', S3' and S4' that are interacting with the octapeptide by regions R4, R3, R2, R1, R1', R2', R3' and R4' respectively. The scissile bond (between R1 and R1') will be hydrolyzed by HIV protease.
== Licensing ==
{{PD-self}}

File:HIV protease active site.jpg

2010-05-02T02:19:02Z

File:HIV protease active site.jpg

2010-05-02T02:16:26Z

Nicole Maille: A schematic representation of substrate bound to the active site of HIV protease. The active site contains eight "subsites," S4, S3, S2, S1, S1', S2', S3' and S4' that are interacting with the octapeptide by regions R4, R3, R2, R1, R1', R2', R3' and R4' r

2010-05-01T02:48:36Z

Nicole Maille:

[[User:Nicole Maille/Sandbox 1]]