J Am Chem Soc. 2005 Oct 12;127(40):13778-9.

Fast peptidyl cis-trans isomerization within the flexible Gly-rich flaps of HIV-1 protease.

Source

Howard Hughes Medical Institute, Center for Theoretical Biological Physics, Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California 92093, USA. dhamelbe@mccammon.ucsd.edu

Abstract

The catalytic aspartyl protease of the HIV-1 virus is a homodimer with two flaps that control access to the active site and are known to be flexible. However, knowledge of the atomistic mechanism of the flexibility is lacking. We show that the Gly-Gly omega-bond in the glycine-rich flap tips undergoes fast cis-trans isomerization on the microsecond to millisecond time scale rather than in the usual seconds. Further study reveals that the unexpectedly fast isomerization is a direct consequence of the beta-hairpin loop structure of the flap tips, which appears to be counterintuitive. After loop formation of a linear peptide containing the Gly-Gly motif, the rate of isomerization is shown to increase by many orders of magnitude.

PMID:: 16201784; [PubMed - indexed for MEDLINE]

Publication Types, MeSH Terms, Substances

Publication Types

MeSH Terms

Substances

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases

GLYCINE - HSDB

Supplemental Content

Save items

Related citations in PubMed

Curling of flap tips in HIV-1 protease as a mechanism for substrate entry and tolerance of drug resistance. [Structure. 2000]
Curling of flap tips in HIV-1 protease as a mechanism for substrate entry and tolerance of drug resistance.
Scott WR, Schiffer CA. Structure. 2000 Dec 15; 8(12):1259-65.
Catalysis of cis/trans isomerization in native HIV-1 capsid by human cyclophilin A. [Proc Natl Acad Sci U S A. 2002]
Catalysis of cis/trans isomerization in native HIV-1 capsid by human cyclophilin A.
Bosco DA, Eisenmesser EZ, Pochapsky S, Sundquist WI, Kern D. Proc Natl Acad Sci U S A. 2002 Apr 16; 99(8):5247-52. Epub 2002 Apr 2.
Rapid structural fluctuations of the free HIV protease flaps in solution: relationship to crystal structures and comparison with predictions of dynamics calculations. [Protein Sci. 2002]
Rapid structural fluctuations of the free HIV protease flaps in solution: relationship to crystal structures and comparison with predictions of dynamics calculations.
Freedberg DI, Ishima R, Jacob J, Wang YX, Kustanovich I, Louis JM, Torchia DA. Protein Sci. 2002 Feb; 11(2):221-32.
Review Glycine rich P-loop motif in deoxyuridine pyrophosphatase. [Curr Protein Pept Sci. 2001]
Review Glycine rich P-loop motif in deoxyuridine pyrophosphatase.
Prasad GS. Curr Protein Pept Sci. 2001 Dec; 2(4):301-11.
Review HIV-1 protease folding and the design of drugs which do not create resistance. [Curr Opin Struct Biol. 2008]
Review HIV-1 protease folding and the design of drugs which do not create resistance.
Broglia R, Levy Y, Tiana G. Curr Opin Struct Biol. 2008 Feb; 18(1):60-6. Epub 2007 Dec 21.

See reviews... See all...

Cited by 19 PubMed Central articles

Protecting High Energy Barriers: A New Equation to Regulate Boost Energy in Accelerated Molecular Dynamics Simulations. [J Chem Theory Comput. 2012]
Protecting High Energy Barriers: A New Equation to Regulate Boost Energy in Accelerated Molecular Dynamics Simulations.
Sinko W, de Oliveira CA, Pierce LC, McCammon JA. J Chem Theory Comput. 2012 Jan 10; 8(1):17-23. Epub 2011 Nov 21.
Review Molecular dynamics simulations and drug discovery. [BMC Biol. 2011]
Review Molecular dynamics simulations and drug discovery.
Durrant JD, McCammon JA. BMC Biol. 2011 Oct 28; 9:71. Epub 2011 Oct 28.
Implementation of Accelerated Molecular Dynamics in NAMD. [Comput Sci Discov. 2011]
Implementation of Accelerated Molecular Dynamics in NAMD.
Wang Y, Harrison CB, Schulten K, McCammon JA. Comput Sci Discov. 2011; 4(1).

See all...

Related information

Related Citations
Calculated set of PubMed citations closely related to the selected article(s) retrieved using a word weight algorithm. Related articles are displayed in ranked order from most to least relevant, with the “linked from” citation displayed first.
Compound (MeSH Keyword)
PubChem chemical compound records that are classified under the same Medical Subject Headings (MeSH) controlled vocabulary as the current articles.
Substance (MeSH Keyword)
PubChem chemical substance (submitted) records that are classified under the same Medical Subject Headings (MeSH) controlled vocabulary as the current articles.
Cited in PMC
Full-text articles in the PubMed Central Database that cite the current articles.

Recent activity

Clear Turn Off Turn On

Fast peptidyl cis-trans isomerization within the flexible Gly-rich flaps of HIV-...
Fast peptidyl cis-trans isomerization within the flexible Gly-rich flaps of HIV-1 protease.
J Am Chem Soc. 2005 Oct 12 ;127(40):13778-9.

PubMed
Pharmaceutical promotions--a free lunch?
Pharmaceutical promotions--a free lunch?
N Engl J Med. 1992 Jul 30 ;327(5):351-3.

PubMed
Infectious ileocecitis--appendicitis mimicking syndrome.
Infectious ileocecitis--appendicitis mimicking syndrome.
Bratisl Lek Listy. 2005 ;106(6-7):201-2.

PubMed
Overlapping and CpG methylation-sensitive protein-DNA interactions at the histon...
Overlapping and CpG methylation-sensitive protein-DNA interactions at the histone H4 transcriptional cell cycle domain: distinctions between two human H4 gene promoters.
Mol Cell Biol. 1992 Jul ;12(7):3273-87.

PubMed
Interaction of dietary composition and PYY gene expression in diet-induced obesi...
Interaction of dietary composition and PYY gene expression in diet-induced obesity in rats.
J Huazhong Univ Sci Technolog Med Sci. 2005 ;25(3):243-6.

PubMed

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

PubMed

Result Filters

Display Settings:

Send to: