Flexibility and function in HIV-1 protease.
HIV protease is a homodimeric protein whose activity is essential to viral function. We have investigated the molecular dynamics of the HIV protease, thought to be important for proteinase function, bound to high affinity inhibitors using NMR techniques. Analysis of 15N spin relaxation parameters, of all but 13 backbone amide sites, reveals the presence of significant internal motions of the protein backbone. In particular, the flaps that cover the proteins active site of the protein have terminal loops that undergo large amplitude motions on the ps to ns time scale, while the tips of the flaps undergo a conformational exchange on the microsecond time scale. This enforces the idea that the flaps of the proteinase are flexible structures that facilitate function by permitting substrate access to and product release from the active site of the enzyme.
Nicholson
L K
LK
Molecular Structural Biology Unit, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
Yamazaki
T
T
Torchia
D A
DA
Grzesiek
S
S
Bax
A
A
Stahl
S J
SJ
Kaufman
J D
JD
Wingfield
P T
PT
Lam
P Y
PY
Jadhav
P K
PK
D000595:Amino Acid Sequence; D001381:Azepines; D001665:Binding Sites; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism; D007532:Isoleucine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008958:Models, Molecular; D009587:Nitrogen Isotopes; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry
D001381:Azepines; D017320:HIV Protease Inhibitors; D009587:Nitrogen Isotopes; C094384:P 9941; D011994:Recombinant Proteins; D007532:Isoleucine; D014508:Urea; D016333:HIV Protease; C085816:DMP 323