These images were made by the students of CHEM 6521
[syllabus] [Kinases and Phosphatases] [Proteases] [Polymerases, Integrases, Transcriptases]
Influenza neuraminidase
This protein (pdb entry: 1mwe ) is shown with six, propeller-like
beta sheets in red. Sialic acid, in yellow spacefill, is bound.
Residues involved in binding are represented as blue sticks while
those suspected in catalysis are represented in green sticks.
A closer look at the binding site is shown
with all residues as sticks. Hydrogen bonds are represented by
straight lines. The catalytic mechanism is not known, but residues
implicated by one model are shown in a separate
image as red sticks. This image was made by Joy Holtvluwer
Ting, School of Biology, Georgia Tech, 1998.
Human Lysozyme C
bound with hydrolyzed (NAG)6
This image shows the 30 residue bacteriocidal protein with 5 non-bundled
a-helices (purple; 1 on the left, 1 in back, 3 overlapping on
the right) and 1 anti-parallel b-sheet (cyan) through the center
forming the active site binding cleft. Hydrolyzes the b(1-4) glycosidic
bond between NAM-NAG of murein in bacterial cell walls and NAG-NAG
of chitin in fungi cell walls. Substrate shown as ball-and-stick.
Invariant residues among type-C lysozymes that are involved in
substrate binding shown as sticks with grey carbon (W64, N60,
Q58). N44, shown with green carbons, hydrogen bonds with the substrate
and is invariant in all type-C lysozymes except in insects where
it is substituted with G. Black carbons indicate catalytic residues.
D52, too far to catalyze the hydrolysis of the 4th saccharide's
C1-O1 bond by Sn2 mechanism, stabilizes the transition-state oxonium
carbocation half-chair conformation in an Sn1 acetal hydrolysis.
E35 then hydroxylates the C1 of the oxonium ion to form the hemiacetal
product. Na ion (orange) located far away from active site in
upper left. Image by Thomas Paxton, School of Chemical Engineering,
Georgia Tech, 1998.
c-Ha-ras p21
The active site of the c-Ha-ras p21 protein (PDB code: 5P21) showing
the bound Gppnp nucleotide (serving as a GTP analog). The ras
p21 protein is a GTP-binding protein that plays a critical role
in intracellular signaling leading to cell growth and proliferation.
Point mutations in the protein structure often cause anomalous
activity leading to cancer. The Gppnp (green stick representation)
ring interacts with Lys117 (red, ball & stick) and Phe28 (blue,
ball & stick) side chains while its phosphates interact with
the P-Loop (cyan ribbon) and magnesium ion (yellow space filling).
This image was made by Kevin Davis, School of Geochemistry, Georgia
Tech, 1998.
p53
A view into the DNA binding domain of p53 (PDB entry: 1tsr) Only
residues involved in DNA binding or zinc coordination are shown.
The DNA is shown as orange backbone. The loops of the p53 protein
that coordinate the zinc molecule and bind the DNA are also shown
in backbone form. The L3 (red) and L2 (grey) loops of p53 coordinate
Zinc molecule (red; spacefilling) using Histidine 179 (grey; stick)
and Cysteine 176, 242, and 238 (yellow; stick) amino acid residues.
Arginine 248 (cyan; stick) and Serine 241 (purple; stick) are
located on the L3 loop of p53 and hydrogen bond to oxygen atoms
on phosphate groups of the DNA backbone at Thymidine 11 (green;
stick) and Guanidine 13 (white; stick), respectively. Displacement
of the zinc atom by organic mercurial compounds will decrease
the stability of the L3-L2 interaction by causing misalignment
of Arginine 248 and Serine 241 and loss of their hydrogen bonding
interactions. This leads to loss of transcription activity by
p53. This image was made by Roy Wade, Jr., School of Biology,
Georgia Tech, 1998.
Cyclooxygenase
The cyclooxygenase active site is located within a long hydrophobic
channel at a region defined by residues arg 120, ser 530 (site
of aspirin acetylation), tyr 385, and glu 524. The second
image is that of an inhibitor, within the active site. It
is unclear how this reacts, some think it blocks the channel --
some think it reacts. New evidence shows different results through
an associated protein. This image was made by Barry Birch, School
of Chemistry and Biochemistry, Georgia Tech, December 1998.
Mammalian Scorpion
Toxin II
(PDB entry: 1ptx) This protein is scorpion toxin II from Androctonus
austalis. It is a 64 residue protein that binds to mammalian sodium
channels, causing paralysis and death at high enough doses. Most
of the residues indicated to be crucial to binding to sodium channels
are located on a knob at the lower left of the image. Positively
charged amino acids are shown in red. Arg 62 and His 64 protrude
furthest from the core of the protein. It is reasonable to expect
such residues to be involved in binding to sodium channels, which
usually handle positively-charged Na+ ions. Mutational analysis
has shown that Asp 8 (blue) and Lys 58 (green) are likely to be
critical to binding. Arg 18 is not in the same region as the rest
of the binding residues, but probably has a major role in binding
also. The purple segment is residues 9 through 12, which together
with residue 8, form a structurally conserved loop found in many
scorpion toxins. This image was made by J High, School of Biology,
Georgia Tech, 1998.
Polymerases, integrases, transcriptases [top]
HIV-1 integrase
A view of the HIV-1 integrase core domain as a dimer (PDB entry:
1bis). The catalytic site is represented
in a conserved D,D-35E motif (shown in stick: green Asp 64, blue
Asp 116, purple Glu 152). These residues are thought to coordinate
a divalent metal ion to facilitate the polynucleotidyl transfer
reaction. This image was made by Carolyn A Haller, School of Biology,
Georgia Tech, 1998.
HIV-1 Reverse
Transcriptase
A view of the HIV-1 reverse transcriptase active site with bound
DNA template-primer showing the interactions between the DNA and
HIV-1 RT. The catalytic residues are colored: D110-blue, Y115-green,
Y183-magenta, M184-cyan, D185-orange, D186-redorange. The double-stranded
DNA template primer close to the catalytic site is represented
in stick, with cpk colors. Here is a view
into the nonnucleotide inhibitor binding site. This binding
site is near the active site consisting of the catalytic residues
Asp 110, Asp 185, Asp 186, but distinct from it. When the Dipyridodiazepinone
Nevirapine nonnucleoside inhibitor (seen in red and sticks) binds,
it repositions the aspartyl residues inactivating the polymerase.
The residues that interact with the inhibitor are shown in ball
and stick representation. Images by Karen Ellis, School of Chemistry
and Biochemistry, Georgia Tech, 1998.
Bacillus
stearothermophilus polymerase
(Bstpol1)
A view of the active site of the Bacillus stearothermophilus
polymerase (PDB entry: 1bpd). This is analogous to the Klenow
fragment of DNA polymerase I in E.coli. The residues of
the active site are shown as sticks (green and purple). The purple
areas represent those residues forming the pocket surrounding
the first base of the DNA template. This image was made by Brooke
Bourdélat-Parks, School of Biology, Georgia Tech, 1998.
Kinases and Phosphatases [top]
Ca2+/calmodulin-dependent
protein kinase I
In this image CaMKI (PDB entry; 1a06) is shown in the autoinactive
form. The pseudosubtrate sequence binds in the substrate recognition
site and inhibits kinase activity. Once calmodulin is activated
by Ca2+, calmodulin binds the adjacent sequence and relieves the
inhibition. ATP binding lobe; blue ribbon, catalytic loop; spacefill,
pseudosubstrate sequence; stick, Phe298; yellow stick, Lys300;
purple stick, Glu102, Ile210, Pro216, Phe104: cyan spacefill.
This image was made by Hosoon Choi, Biology, Georgia Tech, 1998.
Cdk2 with bound ATP
and Mg2+.
A view into the catalytic cleft of Cdk2 with bound ATP and Mg2+
(yellow) (PDB entry; 1hck). Residues that make key contacts with
ATP are rendered as "ball & stick." The N and C
terminal residues are shown as "ball & stick," as
well as Thr 160, colored red, which is an important regulatory
phosphorylation site. Other important structural features are
labeled. A closer view. Images by
Kim Allen, School of Biology, Georgia Tech, 1998.
Beta-Adrenergic Receptor
Kinase 1
This protein (pdb entry: 1bak) is only the Pleckstrin Homology
domain of the beta-adrenergic receptor kinase 1 (BARK1) and was
derived from 20 superimposed NMR structures. The catalytic site
and necessary residues are not well understood. The BARK1 PH domain
is related to the PLC delta PH domain, shown
with ligand inositol triphosphate in space filling, PH domain
is in ribbon representation, and interacting lysine residues are
shown as sticks in green. In another image, only the I3P and interacting
lysines are shown. Interactions of I3P and
BARK1 as deduced from the PLC delta PH domain by x-ray diffraction.
These image were made by Chris Banna, School of Biology, Georgia
Tech, 1998.
Tyrosine Phosphatase 1B
Active site of Protein Tyrosine Phosphatase 1B (PDB entry: 1pty)
complexed with a phosphotyrosine molecule. The phosphotyrosine
has been represented as spacefilling, while the residues required
for catalysis (181, 215-222) are shown as sticks and colored by
CPK. This image was made by Kris Woods, School of Chemistry and
Biochemistry, Georgia Tech, 1998.
Proteases [top]
Thrombin
This image is Thrombin (PDB entry: 1abj), a serine protease. The
catalytic triad is shown in stick format. Its active site, consisting
of Ser195 (cyan), His57 (blue), and Asp102 (red), is very narrow.
The figure also shows the S1 specificity pocket including Asp189
(purple ball and stick) that directs substrate binding. Note the
location and orientation of PPACK (in CPK stick) within the active
site. The Arg of PPACK is directed into the specificity pocket.
View of the catalytic triad, which consists
of ser195 (yellow), his57 (blue) and Asp102 (red). Note the depth
and narrowness of the binding pocket. The nine amino acid base
insert - called the 60loop (cyan) restricts access of macromolecules
to the triad, and therefore increases the specificity. Also shown
is the anion binding site, known as the fibrinogen recognition
site composed of Arg35,67,73,75,77 (blue green patches) where
fibrinogen interacts and is cleaved into the insoluble fibrin
in the coagulation cascade. These images were made by Tope Olubuyide,
School of Chemistry and Biochemistry, Georgia Tech, 1998.
Interleukin-1-b-Converting
Enzyme
Overall view of the topology of Interleukin-1-b-Converting Enzyme
(ICE; PDB entry 1ice), showing the unique a/b structure of the
protein caused by association of two p20/p10 dimers to form a
tetramer. Helical portions are colored green, and b-strands are
colored red. Also shown is a view into the
active site of Interleukin-1-b-Converting Enzyme showing both
the catalytic dyad of Cys 285 and His 237, and the four residues
that make up the Aspartic acid binding pocket (Arg. 341, Arg 179,
Ser 347, and Gln 283). The color scheme is as follows: Cys 285
(red), His 273 (orange), Arg 341 (magenta), Arg 179 (green), Ser
347 (blue), and Gln 283 (yellow). These images was made by Karrie
Adlington, School of Chemistry and Biochemistry, Georgia Tech,
1998.
The NS3 Protease
complexed with NS4A cofactor
This complex is believed to play a central role in the replication
and maturation of HCV. The overall folding is similar to chymotrypsin
in serine protease family. There are two domains, roughly dividing
the protease in halves. Each domain is composed of a b-barrel
and two short a-helices. The NS4 is bound within the N-terminal
Domain. (NS4A cofactor is green, Zn metal is purple, b-barrel
is yellow and a-helix is magneta. The active
site of NS3-protease is similar to chymotrypsin in the serine
protease family. The proposed catalytic triad His-57, Asp-81,
and Ser 139. The main determinant of the substrate binding is
phenylalanine 154, with an additional minor role for alanine 157.
This image was made by Juliana Gheura, School of Chemistry and
Biochemistry, Georgia Tech, 1998.
Factor X
Factor X is involved in blood clotting (PDB entry: 1whe). Active
site residues are shown in spacefilling, with Ser 195 red; His
57 blue; and Asp 102 green. The backbone is yellow. The
catalytic triad. These images were made by Amy Larson, School
of Chemistry and Biochemistry, Georgia Tech, 1998.
Cathepsin B
View into the active site of Cathepsin B (PDB entry: 1csb). The
active site residues are represented as spacefilled models, colored
in CPK colors. The inhibitor, CA030, is shown bound to the catalytic
Cys 29 residue and is in ball and stick format with CPK colors.
This image was made by Brian Rukamp, School of Chemistry and Biochemistry,
Georgia Tech, 1998.
Cathepsin D
The active site of cathepsin D (PDB entry: 1lya) is shown here
bound to an inhibitor, pepstatin. Pepstatin lies in the active
site cleft of cathepsin D, where it is hydrogen bonded to residues
in the active site, including two aspartic acid residues which
provide the catalytic activity. This image was made by Shelley
Howerton, School of Chemistry and Biochemistry, Georgia Tech,
1998.
Carboxypeptidase
A
Carboxypeptidase A, a digestive enzyme, is shown complexed with
the L-benzyl succinate inhibitor (PDB entry: 1cbx). Active
site interactions. The zinc atom is shown in blue, the inhibitor
in red, the alpha helices in green and the beta sheet in yellow.
In a closer view of the active site, the important residues for
catalysis are labeled and shown in green. Images by Karen Lambert,
School of Textile and Fiber Engineering, Georgia Tech, 1998.
HIV protease
A view into the active site of HIV-1 protease complexed with the
inhibitor A77003 (R,S) (PDB entry; 1hvi). The inhibitor is in
between the water molecule and the active aspartic acid residues,
preventing catalysis. The inhibitor is purple, active residues
Asp 25 and Asp 25' are Orange, the oxygen atoms are red, the water
molecule is cyan, and the rest of protein is green. Image by Dave
Kim, School of Chemistry and Biochemistry, Georgia Tech, 1998.
Acetylcholinesterase
with bound acetylcholine
The catalytic triad of acetylcholinesterase from Torpedo californica
(PDB entry: 2ace) with bound acetylcholine. The acetylcholine
was inserted by modeling and is covalently attached to Ser200
in the first step of the serine esterase mechanism. The covalent
bond is not shown in the image. The three residues, Ser200, Glu327,
and His440 are labeled accordingly and colored by atom type; acetylcholine
is labeled and colored the same way. This catalytic triad functions
in an identical manner to the serine protease mechanism described
in Voet and Voet "Biochemistry" p. 395, with only a
structural difference in that glutamic acid is substituted for
aspartic acid. This image was created by Bryan Herger, School
of Chemistry and Biochemistry, Georgia Tech, 1998.
