2nph: Difference between revisions

Revision as of 19:09, 21 February 2008

Crystal structure of HIV1 protease in situ product complex

OverviewOverview

HIV-1 protease is an effective target for designing drugs against AIDS, and structural information about the true transition state and the correct mechanism can provide important inputs. We present here the three-dimensional structure of a bi-product complex between HIV-1 protease and the two cleavage product peptides AETF and YVDGAA. The structure, refined against synchrotron data to 1.65 A resolution, shows the occurrence of the cleavage reaction in the crystal, with the product peptides still held in the enzyme active site. The separation between the scissile carbon and nitrogen atoms is 2.67 A, which is shorter than a normal van der Waal separation, but it is much longer than a peptide bond length. The substrate is thus in a stage just past the G'Z intermediate described in Northrop's mechanism [Northrop DB (2001) Acc Chem Res 34:790-797]. Because the products are generated in situ, the structure, by extrapolation, can give insight into the mechanism of the cleavage reaction. Both oxygens of the generated carboxyl group form hydrogen bonds with atoms at the catalytic center: one to the OD2 atom of a catalytic aspartate and the other to the scissile nitrogen atom. The latter hydrogen bond may have mediated protonation of scissile nitrogen, triggering peptide bond cleavage. The inner oxygen atoms of the catalytic aspartates in the complex are 2.30 A apart, indicating a low-barrier hydrogen bond between them at this stage of the reaction, an observation not included in Northrop's proposal. This structure forms a template for designing mechanism-based inhibitors.

About this StructureAbout this Structure

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

ReferenceReference

Crystal structure of HIV-1 protease in situ product complex and observation of a low-barrier hydrogen bond between catalytic aspartates., Das A, Prashar V, Mahale S, Serre L, Ferrer JL, Hosur MV, Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18464-9. Epub 2006 Nov 20. PMID:17116869

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 '''Crystal structure of HIV1 protease in situ product complex'''<br />
 ==Overview==
-HIV-1 protease is an effective target for designing drugs against AIDS, and structural information about the true transition state and the correct, mechanism can provide important inputs. We present here the, three-dimensional structure of a bi-product complex between HIV-1 protease, and the two cleavage product peptides AETF and YVDGAA. The structure, refined against synchrotron data to 1.65 A resolution, shows the, occurrence of the cleavage reaction in the crystal, with the product, peptides still held in the enzyme active site. The separation between the, scissile carbon and nitrogen atoms is 2.67 A, which is shorter than a, normal van der Waal separation, but it is much longer than a peptide bond, length. The substrate is thus in a stage just past the G'Z intermediate, described in Northrop's mechanism [Northrop DB (2001) Acc Chem Res, 34:790-797]. Because the products are generated in situ, the structure, by, extrapolation, can give insight into the mechanism of the cleavage, reaction. Both oxygens of the generated carboxyl group form hydrogen bonds, with atoms at the catalytic center: one to the OD2 atom of a catalytic, aspartate and the other to the scissile nitrogen atom. The latter hydrogen, bond may have mediated protonation of scissile nitrogen, triggering, peptide bond cleavage. The inner oxygen atoms of the catalytic aspartates, in the complex are 2.30 A apart, indicating a low-barrier hydrogen bond, between them at this stage of the reaction, an observation not included in, Northrop's proposal. This structure forms a template for designing, mechanism-based inhibitors.
+HIV-1 protease is an effective target for designing drugs against AIDS, and structural information about the true transition state and the correct mechanism can provide important inputs. We present here the three-dimensional structure of a bi-product complex between HIV-1 protease and the two cleavage product peptides AETF and YVDGAA. The structure, refined against synchrotron data to 1.65 A resolution, shows the occurrence of the cleavage reaction in the crystal, with the product peptides still held in the enzyme active site. The separation between the scissile carbon and nitrogen atoms is 2.67 A, which is shorter than a normal van der Waal separation, but it is much longer than a peptide bond length. The substrate is thus in a stage just past the G'Z intermediate described in Northrop's mechanism [Northrop DB (2001) Acc Chem Res 34:790-797]. Because the products are generated in situ, the structure, by extrapolation, can give insight into the mechanism of the cleavage reaction. Both oxygens of the generated carboxyl group form hydrogen bonds with atoms at the catalytic center: one to the OD2 atom of a catalytic aspartate and the other to the scissile nitrogen atom. The latter hydrogen bond may have mediated protonation of scissile nitrogen, triggering peptide bond cleavage. The inner oxygen atoms of the catalytic aspartates in the complex are 2.30 A apart, indicating a low-barrier hydrogen bond between them at this stage of the reaction, an observation not included in Northrop's proposal. This structure forms a template for designing mechanism-based inhibitors.
 ==About this Structure==
-NPH is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=2NPH OCA].
+NPH is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. 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=2NPH OCA].
 ==Reference==
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 [[Category: Single protein]]
 [[Category: Das, A.]]
-[[Category: Hosur, M.V.]]
+[[Category: Hosur, M V.]]
 [[Category: Prashar, V.]]
 [[Category: anti-parallel beta sheet]]
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