2fns: Difference between revisions

Revision as of 18:23, 21 February 2008

Crystal structure of wild-type inactive (D25N) HIV-1 protease complexed with wild-type HIV-1 NC-p1 substrate.

OverviewOverview

Human immunodeficiency virus type 1 (HIV-1) protease processes and cleaves the Gag and Gag-Pol polyproteins, allowing viral maturation, and therefore is an important target for antiviral therapy. Ligand binding occurs when the flaps open, allowing access to the active site. This flexibility in flap geometry makes trapping and crystallizing structural intermediates in substrate binding challenging. In this study, we report two crystal structures of two HIV-1 protease variants bound with their corresponding nucleocapsid-p1 variant. One of the flaps in each of these structures exhibits an unusual "intermediate" conformation. Analysis of the flap-intermediate and flap-closed crystal structures reveals that the intermonomer flap movements may be asynchronous and that the flap which wraps over the P3 to P1 (P3-P1) residues of the substrate might close first. This is consistent with our hypothesis that the P3-P1 region is crucial for substrate recognition. The intermediate conformation is conserved in both the wild-type and drug-resistant variants. The structural differences between the variants are evident only when the flaps are closed. Thus, a plausible structural model for the adaptability of HIV-1 protease to recognize substrates in the presence of drug-resistant mutations has been proposed.

About this StructureAbout this Structure

2FNS is a Single protein structure of sequence from Human immunodeficiency virus 1 with and as ligands. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.

ReferenceReference

Mechanism of substrate recognition by drug-resistant human immunodeficiency virus type 1 protease variants revealed by a novel structural intermediate., Prabu-Jeyabalan M, Nalivaika EA, Romano K, Schiffer CA, J Virol. 2006 Apr;80(7):3607-16. PMID:16537628

Page seeded by OCA on Thu Feb 21 17:23:20 2008

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 ==Overview==
-Human immunodeficiency virus type 1 (HIV-1) protease processes and cleaves, the Gag and Gag-Pol polyproteins, allowing viral maturation, and therefore, is an important target for antiviral therapy. Ligand binding occurs when, the flaps open, allowing access to the active site. This flexibility in, flap geometry makes trapping and crystallizing structural intermediates in, substrate binding challenging. In this study, we report two crystal, structures of two HIV-1 protease variants bound with their corresponding, nucleocapsid-p1 variant. One of the flaps in each of these structures, exhibits an unusual "intermediate" conformation. Analysis of the, flap-intermediate and flap-closed crystal structures reveals that the, intermonomer flap movements may be asynchronous and that the flap which, wraps over the P3 to P1 (P3-P1) residues of the substrate might close, first. This is consistent with our hypothesis that the P3-P1 region is, crucial for substrate recognition. The intermediate conformation is, conserved in both the wild-type and drug-resistant variants. The, structural differences between the variants are evident only when the, flaps are closed. Thus, a plausible structural model for the adaptability, of HIV-1 protease to recognize substrates in the presence of, drug-resistant mutations has been proposed.
+Human immunodeficiency virus type 1 (HIV-1) protease processes and cleaves the Gag and Gag-Pol polyproteins, allowing viral maturation, and therefore is an important target for antiviral therapy. Ligand binding occurs when the flaps open, allowing access to the active site. This flexibility in flap geometry makes trapping and crystallizing structural intermediates in substrate binding challenging. In this study, we report two crystal structures of two HIV-1 protease variants bound with their corresponding nucleocapsid-p1 variant. One of the flaps in each of these structures exhibits an unusual "intermediate" conformation. Analysis of the flap-intermediate and flap-closed crystal structures reveals that the intermonomer flap movements may be asynchronous and that the flap which wraps over the P3 to P1 (P3-P1) residues of the substrate might close first. This is consistent with our hypothesis that the P3-P1 region is crucial for substrate recognition. The intermediate conformation is conserved in both the wild-type and drug-resistant variants. The structural differences between the variants are evident only when the flaps are closed. Thus, a plausible structural model for the adaptability of HIV-1 protease to recognize substrates in the presence of drug-resistant mutations has been proposed.
 ==About this Structure==
@@ Line 14: / Line 14: @@
 [[Category: Human immunodeficiency virus 1]]
 [[Category: Single protein]]
-[[Category: Nalivaika, E.A.]]
+[[Category: Nalivaika, E A.]]
 [[Category: Prabu-Jeyabalan, M.]]
-[[Category: Schiffer, C.A.]]
+[[Category: Schiffer, C A.]]
 [[Category: ACT]]
 [[Category: PO4]]
@@ Line 26: / Line 26: @@
 [[Category: substrate recognition]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 17:25:55 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:23:20 2008''