1kzk
From Proteopedia
(New page: 200px<br /> <applet load="1kzk" size="450" color="white" frame="true" align="right" spinBox="true" caption="1kzk, resolution 1.09Å" /> '''JE-2147-HIV Proteas...) |
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| - | [[Image:1kzk.gif|left|200px]]<br /> | + | [[Image:1kzk.gif|left|200px]]<br /><applet load="1kzk" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1kzk" size=" | + | |
caption="1kzk, resolution 1.09Å" /> | caption="1kzk, resolution 1.09Å" /> | ||
'''JE-2147-HIV Protease Complex'''<br /> | '''JE-2147-HIV Protease Complex'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The structure of HIV protease (HIV Pr) bound to JE-2147 (also named AG1776 | + | The structure of HIV protease (HIV Pr) bound to JE-2147 (also named AG1776 or KNI-764) is determined here to 1.09 A resolution. This highest-resolution structure for HIV Pr allows refinement of anisotropic displacement parameters (ADPs) for all atoms. Clustering based on the directional information in ADPs defines two sets of subdomains such that within each set, subdomains undergo similar anisotropic motion. These sets are (a) the core of monomer A grouped with both substrate-binding flaps and (b) the core of monomer B coupled to both catalytic aspartates (25A/B). The four-stranded beta-sheet (1-4 A/B and 95-99 A/B) that forms a significant part of the dimer interface exhibits large anisotropic amplitudes that differ from those of the other sets of subdomains. JE-2147 is shown here to be a picomolar inhibitor (K(i) = 41 +/- 18 pM). The structure is used to interpret the mechanism of association of JE-2147, a second-generation inhibitor for which binding is enthalpically driven, with respect to first-generation inhibitors for which binding is predominantly entropically driven [Velazquez-Campoy, A., et al. (2001) Arch. Biochem. Biophys. 390, 169-175]. Relative to the entropically driven inhibitor complexes, the JE-2147-HIV Pr complex exhibits an approximately 0.5 A movement of the substrate flaps in toward the substrate, suggesting a more compatible enthalpically driven association. Domains of the protease identified by clustering of ADPs also suggest a model of enthalpy-entropy compensation for all HIV Pr inhibitors in which dynamic coupling of the flaps is offset by an increased level of motion of the beta-sheet domain of the dimer interface (1-4 A/B and 95-99 A/B). |
==About this Structure== | ==About this Structure== | ||
| - | 1KZK is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus Human immunodeficiency virus] with JE2, CL and EDO as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/HIV-1_retropepsin HIV-1 retropepsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.16 3.4.23.16] Full crystallographic information is available from [http:// | + | 1KZK is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus Human immunodeficiency virus] with <scene name='pdbligand=JE2:'>JE2</scene>, <scene name='pdbligand=CL:'>CL</scene> and <scene name='pdbligand=EDO:'>EDO</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/HIV-1_retropepsin HIV-1 retropepsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.16 3.4.23.16] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1KZK OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Human immunodeficiency virus]] | [[Category: Human immunodeficiency virus]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Craik, C | + | [[Category: Craik, C S.]] |
| - | [[Category: Dauber, D | + | [[Category: Dauber, D S.]] |
| - | [[Category: Endres, N | + | [[Category: Endres, N F.]] |
| - | [[Category: Reiling, K | + | [[Category: Reiling, K K.]] |
| - | [[Category: Stroud, R | + | [[Category: Stroud, R M.]] |
[[Category: CL]] | [[Category: CL]] | ||
[[Category: EDO]] | [[Category: EDO]] | ||
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[[Category: hiv protease complex]] | [[Category: hiv protease complex]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:39:37 2008'' |
Revision as of 11:39, 21 February 2008
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JE-2147-HIV Protease Complex
Overview
The structure of HIV protease (HIV Pr) bound to JE-2147 (also named AG1776 or KNI-764) is determined here to 1.09 A resolution. This highest-resolution structure for HIV Pr allows refinement of anisotropic displacement parameters (ADPs) for all atoms. Clustering based on the directional information in ADPs defines two sets of subdomains such that within each set, subdomains undergo similar anisotropic motion. These sets are (a) the core of monomer A grouped with both substrate-binding flaps and (b) the core of monomer B coupled to both catalytic aspartates (25A/B). The four-stranded beta-sheet (1-4 A/B and 95-99 A/B) that forms a significant part of the dimer interface exhibits large anisotropic amplitudes that differ from those of the other sets of subdomains. JE-2147 is shown here to be a picomolar inhibitor (K(i) = 41 +/- 18 pM). The structure is used to interpret the mechanism of association of JE-2147, a second-generation inhibitor for which binding is enthalpically driven, with respect to first-generation inhibitors for which binding is predominantly entropically driven [Velazquez-Campoy, A., et al. (2001) Arch. Biochem. Biophys. 390, 169-175]. Relative to the entropically driven inhibitor complexes, the JE-2147-HIV Pr complex exhibits an approximately 0.5 A movement of the substrate flaps in toward the substrate, suggesting a more compatible enthalpically driven association. Domains of the protease identified by clustering of ADPs also suggest a model of enthalpy-entropy compensation for all HIV Pr inhibitors in which dynamic coupling of the flaps is offset by an increased level of motion of the beta-sheet domain of the dimer interface (1-4 A/B and 95-99 A/B).
About this Structure
1KZK is a Single protein structure of sequence from Human immunodeficiency virus with , and as ligands. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.
Reference
Anisotropic dynamics of the JE-2147-HIV protease complex: drug resistance and thermodynamic binding mode examined in a 1.09 A structure., Reiling KK, Endres NF, Dauber DS, Craik CS, Stroud RM, Biochemistry. 2002 Apr 9;41(14):4582-94. PMID:11926820
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