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1rpi

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{{STRUCTURE_1rpi| PDB=1rpi | SCENE= }}
{{STRUCTURE_1rpi| PDB=1rpi | SCENE= }}
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'''Crystal structures of a Multidrug-Resistant HIV-1 Protease Reveal an Expanded Active Site Cavity'''
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===Crystal structures of a Multidrug-Resistant HIV-1 Protease Reveal an Expanded Active Site Cavity===
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==Overview==
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The goal of this study was to use X-ray crystallography to investigate the structural basis of resistance to human immunodeficiency virus type 1 (HIV-1) protease inhibitors. We overexpressed, purified, and crystallized a multidrug-resistant (MDR) HIV-1 protease enzyme derived from a patient failing on several protease inhibitor-containing regimens. This HIV-1 variant contained codon mutations at positions 10, 36, 46, 54, 63, 71, 82, 84, and 90 that confer drug resistance to protease inhibitors. The 1.8-angstrom (A) crystal structure of this MDR patient isolate reveals an expanded active-site cavity. The active-site expansion includes position 82 and 84 mutations due to the alterations in the amino acid side chains from longer to shorter (e.g., V82A and I84V). The MDR isolate 769 protease "flaps" stay open wider, and the difference in the flap tip distances in the MDR 769 variant is 12 A. The MDR 769 protease crystal complexes with lopinavir and DMP450 reveal completely different binding modes. The network of interactions between the ligands and the MDR 769 protease is completely different from that seen with the wild-type protease-ligand complexes. The water molecule-forming hydrogen bonds bridging between the two flaps and either the substrate or the peptide-based inhibitor are lacking in the MDR 769 clinical isolate. The S1, S1', S3, and S3' pockets show expansion and conformational change. Surface plasmon resonance measurements with the MDR 769 protease indicate higher k(off) rates, resulting in a change of binding affinity. Surface plasmon resonance measurements provide k(on) and k(off) data (K(d) = k(off)/k(on)) to measure binding of the multidrug-resistant protease to various ligands. This MDR 769 protease represents a new antiviral target, presenting the possibility of designing novel inhibitors with activity against the open and expanded protease forms.
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(as it appears on PubMed at http://www.pubmed.gov), where 14990731 is the PubMed ID number.
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{{ABSTRACT_PUBMED_14990731}}
==About this Structure==
==About this Structure==
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[[Category: Multi-drug resistance]]
[[Category: Multi-drug resistance]]
[[Category: Polyprotein]]
[[Category: Polyprotein]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 07:45:33 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 12:44:36 2008''

Revision as of 09:44, 28 July 2008

Image:1rpi.png

Template:STRUCTURE 1rpi

Crystal structures of a Multidrug-Resistant HIV-1 Protease Reveal an Expanded Active Site Cavity

Template:ABSTRACT PUBMED 14990731

About this Structure

1RPI is a Single protein structure of sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA.

Reference

Crystal structures of a multidrug-resistant human immunodeficiency virus type 1 protease reveal an expanded active-site cavity., Logsdon BC, Vickrey JF, Martin P, Proteasa G, Koepke JI, Terlecky SR, Wawrzak Z, Winters MA, Merigan TC, Kovari LC, J Virol. 2004 Mar;78(6):3123-32. PMID:14990731

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