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FIGUR4E- 20 Constructingla rge motifs from smallero nes.

T he o/B
barreli s a commonlyo ccurringm otifc onstructefdro m repetitionosf
theB -a-B loop motif fhis a/B barreli s a domaino f pyruvatek inase( a
glycolytice nzymef)r omr abbit( derivedfr omp DB lD l pKN).
(Fig. 4-20). In ttus structure, each parallel B segment
is attachedt o its neighborb y an a-helicals egment.A ll
connectionsa rer ight-handedT. he o,lpbarrelisf oundi n
many enzyrnes, often with a binding site (for a cofactor
or substrate)in the form of a pocketn earo ne end of the
barrel. Note that domains with similar folding patterns
are said to have the same motif even though their constituent
a helices and B sheets may differ in length.
ProteMino tifAs reth eB asfiso rP rotein
StructuI Cral assciafit ion
$ ProteinA rchitecture-TertiarSy tructureo f LargeG lobularp roteins,
lV.S tructuralC lassificationo f proteinsA s we have seen,
understandingth e complexitieso f tertiary structurei s
made easierb y considerings ubstructuresT. akingt his
FIGURE4- 21 Organizationo f proteinsb asedo n motifs. Shown
herea rej usta few of the hundredso f knowns tablem otifsT. heya re
divided into four classesa: ll a, all B, a/B, anda * p. Structural
classificatiodna taf rom the SCOp( StructuraCl lassificatioonf pro_
teins)d atabase(h ttp://scomp rc-lmbc am.acu k/scop)a re alsop ro_
idea further, researihers have organized the complete
contentso fprotein databasesa ccordingt o hierarchical
Ievelso f structure.A ll of these databasesre ly on data
and information deposited in the Protein Data Bank.
The Structural Classificationo f Proteins (SCOP)d atabase
is a good example of this important trend in biochemistry.
At the highest level of classification, the
SCO P database( http ://scop.mrc-lmbc.a m.a c.u k/scop)
borrows a scheme already in common use, with four
classes of protein structure: all c, all F, qlg (with a
and B segmentsin terspersedo r alternating),a nd c +
p (with a andB regionss omewhats egregated)E. ach
class includes tens to hundreds of different folding
arrangements (motifs), built up from increasingly
identifiable substructures. Some of the substructure
arrangements are very common, others have been
found in just one protein. Figure 4-21 shows a variety
of motifs arrayed among the four classes of protein
structure; this is just a minute sample of the hundreds
of known motifs. The number of folding patterns is not
infinite, however. As the rate at which new protein
structuresa re elucidatedh asi ncreasedt,h e fraction of
those structures containing a new motif has steadily
declined. Fewer than 1,000 different folds or motifs
may exist in all. Figure 4-21 also shows how proteins
can be organizedb asedo n the presenceo f the various
motifs. The top two levels of organization,c lass and
fold, are purely structural. Below the fold level (see
color key in Fig. 4-21), categorizationis basedo n evolutionary
relationships.
Many examples of recurring domain or motif structures
are availablea, nd theser evealt hat protein tertiary
structure is more reliably conserved than amino
acid sequence. The comparison of protein structures
can thus provide much information about evolution.
vided (seet he color key).T he PDB identifier( listedf irst for each
structure)i s the unique accessionc ode given to each structure
archivedi n the ProteinD ata Bank( www.rcsb.orgf)h. e a/B bArrel
(seeF ig.4 -2O)i s anotherp articularlyc ommona /B motil.
(Figure continues on facing page.)

AntibodiHesa vTew old enticAaln tigen-BindSinitge s


Immunoglobulin G (IgG) is the major class of antibody
molecule and one of the most abundant proteins in
the blood serurn. IgG has four po\peptide chains: two
large ones, called heavy chains, and two light chains,
linked by noncovalent and disulflde bonds into a complexof
M,150,000. The heavy chains of an IgG molecule
interact at one end, then branch to interact separately
with the light chains, forming a Y-shaped molecule
(Fig. 5-2f ). At the "hinges"s eparatingth e baseo f an
IgG molecule from its branches, the immunoglobulin can
be cleaved with proteases. Cleavage with the protease
papainl iberatest he basalf ragment,c alledF c becauseit
usually crystallizes readily, and the two branches, called
Fab, the antigen-binding fragments. Each branch has a
single antigen-binding site.
modelo f the firstc ompletel gC moleculet o be crystallizeda nd structurallya
nalyzed(P DBl D l lCT).A lthoughth e moleculeh ast wo identicalh
eavyc hains( twos hadeso f blue)a ndt wo identicalli ghtc hains
(two shadeso f red), it crystallizedi n the asymmetricc onformation
shownh ere.C onformationfalle xibilitym ayb e importantto thef unction
of immunoglobulins.
(a)
Papain
Cleavage

TheI nulast$, leartinfno 4r,chani!r{rcnq *ire:f ,4*t-l$l rns


Another glycolytic enzFne, enolase, catalyzes the reversible
dehydration of 2-phosphoglycerateto phosphoenolpyruvate:
in relationto theM g2+i ons,L ys3aasn, dC lu2rl in thee nolasea ctives ite.
Nitrogeni s showni n blue,p hosphorusin orange;h ydrogena tomsa re
nots hown( PDBl D lONE).
However, in the enzyme active site, 2-phosphoglycerate
undergoes strong ionic interactions with two
bound Mg2* ions (Fig. 6-23b), making the C-2 proton
more acidic (lowering the pKr) and easier to abstract.
Hydrogen bonding to other active-site amino acid
residues also contributes to the overall mechanism.
The various interactions effectively stabilize both the
enolate intermediate and the transition state preceding
its formation.
Lysuryn[hree sT woS uccessNivuec leophilic
[}isplacemfieenatc tions
Lysozyme is a natural antibacterial agent found in tears
and egg whites. The hen egg white lysozyme (M,14,296)
is a monomer with 129 amino acid residues. This was the
first erzyme to have its three-dimensionasl tructure determined,
by David Phillips and colleaguesin 1965.T he
structure revealed four stabilizing disul-fldeb onds and
a cleft containing the active site (FiS. 6-24a). More
than flve decades of investigations have provided a detailed
picture of the structure and activity of the enz5.'rne,
and an interesting story of how biochemical science

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