From Proteopedia
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| - | [[Image:2qhy.jpg|left|200px]] | + | {{Seed}} |
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| | {{STRUCTURE_2qhy| PDB=2qhy | SCENE= }} | | {{STRUCTURE_2qhy| PDB=2qhy | SCENE= }} |
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| - | '''Crystal Structure of protease inhibitor, MIT-1-AC86 in complex with wild type HIV-1 protease'''
| + | ===Crystal Structure of protease inhibitor, MIT-1-AC86 in complex with wild type HIV-1 protease=== |
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| - | ==Overview==
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| - | The acquisition of drug-resistant mutations by infectious pathogens remains a pressing health concern, and the development of strategies to combat this threat is a priority. Here we have applied a general strategy, inverse design using the substrate envelope, to develop inhibitors of HIV-1 protease. Structure-based computation was used to design inhibitors predicted to stay within a consensus substrate volume in the binding site. Two rounds of design, synthesis, experimental testing, and structural analysis were carried out, resulting in a total of 51 compounds. Improvements in design methodology led to a roughly 1000-fold affinity enhancement to a wild-type protease for the best binders, from a Ki of 30-50 nM in round one to below 100 pM in round two. Crystal structures of a subset of complexes revealed a binding mode similar to each design that respected the substrate envelope in nearly all cases. All four best binders from round one exhibited broad specificity against a clinically relevant panel of drug-resistant HIV-1 protease variants, losing no more than 6-13-fold affinity relative to wild type. Testing a subset of second-round compounds against the panel of resistant variants revealed three classes of inhibitors: robust binders (maximum affinity loss of 14-16-fold), moderate binders (35-80-fold), and susceptible binders (greater than 100-fold). Although for especially high-affinity inhibitors additional factors may also be important, overall, these results suggest that designing inhibitors using the substrate envelope may be a useful strategy in the development of therapeutics with low susceptibility to resistance. | + | The line below this paragraph, {{ABSTRACT_PUBMED_18412349}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 18412349 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_18412349}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Hydrolase]] | | [[Category: Hydrolase]] |
| | [[Category: Protease inhibitor]] | | [[Category: Protease inhibitor]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu May 22 22:27:49 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 11:32:25 2008'' |
Revision as of 08:32, 28 July 2008
Template:STRUCTURE 2qhy
Crystal Structure of protease inhibitor, MIT-1-AC86 in complex with wild type HIV-1 protease
Template:ABSTRACT PUBMED 18412349
About this Structure
2QHY is a Single protein structure of sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA.
Reference
HIV-1 protease inhibitors from inverse design in the substrate envelope exhibit subnanomolar binding to drug-resistant variants., Altman MD, Ali A, Reddy GS, Nalam MN, Anjum SG, Cao H, Chellappan S, Kairys V, Fernandes MX, Gilson MK, Schiffer CA, Rana TM, Tidor B, J Am Chem Soc. 2008 May 14;130(19):6099-113. Epub 2008 Apr 16. PMID:18412349
Page seeded by OCA on Mon Jul 28 11:32:25 2008
