1hbv

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[[Image:1hbv.gif|left|200px]]
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==Overview==
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{{ABSTRACT_7650677}}
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We have previously reported (Newlander et al., J. Med. Chem. 1993, 36, 2321-2331) the design of human immunodeficiency virus type 1 (HIV-1) protease inhibitors incorporating C7 mimetics that lock three amino acid residues of a peptide sequence into a gamma-turn. The design of one such compound, SB203238, was based on X-ray structures of reduced amide aspartyl protease inhibitors. It incorporates a gamma-turn mimetic in the P2-P1' position, where the carbonyl of the C7 ring is replaced with an sp3 methylene group yielding a constrained reduced amide. It shows competitive inhibition with Ki = 430 nM at pH 6.0. The three-dimensional structure of SB203238 bound to the active site of HIV-1 protease has been determined at 2.3 A resolution by X-ray diffraction and refined to a crystallographic R-factor (R = sigma magnitude of Fo magnitude of - magnitude of Fc magnitude of /sigma magnitude of Fo magnitude of, where Fo and Fc are the observed and calculated structure factor amplitudes, respectively) of 0.177. The inhibitor lies in an extended conformation in the active site; however, because of the constrained geometry of the C7 ring, it maintains fewer hydrogen bonds with the protein than in most other HIV-1 protease-inhibitor complexes. More importantly, the inhibitor binds to the enzyme differently than predicted in its design, by binding with the P2-P1' alpha-carbon atoms shifted by approximately one-half a residue toward the N-terminus from their presumed positions. This study illustrates the importance of structural information in an approach to rational drug design.
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==About this Structure==
==About this Structure==
1HBV is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. The following page contains interesting information on the relation of 1HBV with [[http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb29_1.html Penicillin-binding Proteins]]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1HBV OCA].
1HBV is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. The following page contains interesting information on the relation of 1HBV with [[http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb29_1.html Penicillin-binding Proteins]]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1HBV OCA].
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==Reference==
 
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A check on rational drug design: crystal structure of a complex of human immunodeficiency virus type 1 protease with a novel gamma-turn mimetic inhibitor., Hoog SS, Zhao B, Winborne E, Fisher S, Green DW, DesJarlais RL, Newlander KA, Callahan JF, Moore ML, Huffman WF, et al., J Med Chem. 1995 Aug 18;38(17):3246-52. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/7650677 7650677]
 
[[Category: Human immunodeficiency virus 1]]
[[Category: Human immunodeficiency virus 1]]
[[Category: Penicillin-binding Proteins]]
[[Category: Penicillin-binding Proteins]]
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[[Category: Abdel-Meguid, S.]]
[[Category: Abdel-Meguid, S.]]
[[Category: Hoog, S.]]
[[Category: Hoog, S.]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 18:40:33 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Jun 26 17:27:38 2008''

Revision as of 14:27, 26 June 2008

Image:1hbv.png

Template:STRUCTURE 1hbv

A CHECK ON RATIONAL DRUG DESIGN. CRYSTAL STRUCTURE OF A COMPLEX OF HIV-1 PROTEASE WITH A NOVEL GAMMA-TURN MIMETIC


Template:ABSTRACT 7650677

About this Structure

1HBV is a Single protein structure of sequence from Human immunodeficiency virus 1. The following page contains interesting information on the relation of 1HBV with [Penicillin-binding Proteins]. Full crystallographic information is available from OCA.

Page seeded by OCA on Thu Jun 26 17:27:38 2008

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