An Introduction to Structural

Biology

Ming-Jing Hwang ( 黃明經 )

中研院生醫所 N121 (02) 2789-9033
http://gln.ibms.sinica.edu.tw/
Pre-lecture readings
 “The structure of life” http://
publications.nigms.nih.gov/structlife/
 Carl Branden & John Tooze “Introduction
to protein structure”
Why structure?
“The structures of life” (NIGMS) & “Molecule of the Month” (PDB)
Know any Nobel structural
biologist?
http://www.imb-jena.de/IMAGE_NOBEL.html
Structure & function of potassium channel

MacKinnon, 1998 (2003 Nobelist)

What are the experimental methods?
Nature 2000
How many have been solved?
PDB: http://www.rcsb.org/pdb
How many more are needed?
How many proteins are there?
Gerstein & Hegyi, 1998
Is structural genomics the solution?
How?
Structural Genomics: solving fold representatives
Structural genomics and drug design

Baker & Sali, 2001

Nat. Struct. Biol. 2001
Assessing the Progress of SG

1 Nov. 2002, Science

Nature, 2005
PSI Structure Statistics 2002-2003
 Unique structures (30% seq. ID)
PSI 70%
PDB 10%
 New folds
PSI 12%
PDB 3%

NIGMS Protein Structure Initiative

What are the organization principles
of protein structures?
How to classify protein structures?
Hierarchy of protein structures
A. P. Singh
 Classification databases
CATH Class, Architecture, Topolgy, and Homologous
superfamily, a hierarchical classification of protein
domain structures
http://www.biochem.ucl.ac.uk/bsm/cath_new/
SCOP Structural Classification Of Proteins: augmented
manual classification
http://scop.mrc-lmb.cam.ac.uk/scop/
CATH
Class: SSE composition
& packing

Architecture: overall
shape of domain, ignore
SSE connectivity

Topology (Fold):
consider connectivity

Homologous
superfamily: a common
ancestor Singh
Assignment of Class
 All α or All β (could be subjective)
 α / β (βαβ unit) or α + β
 Other classes
Class assignment could be subjective
Alpha structures
Ridges and grooves

C-beta
4 3
Ridge-in-groove interaction

3
Beta structures

Superoxide dimutase
Alpha/beta structures

Closed barrel Open twisted sheet

B-a-b motif

(barrel) (sheet)
a/b vs. a+b
Assignment of Fold
 Defined by the number, type, and
arrangement of SSEs
 Connectivity (e.g. circular permutation,
scrambled proteins)
Assignment of Superfamily
 Homologous even in the absence of significant
sequence similarity
- certain level of structural similarity
- unusual structural features
- low but significant sequence similarity from
structural alignment
- key active site residues
- sequence similarity bridges
 Divergence vs. convergence
Divergent vs. convergent evolution
 Divergent evolution: decent from a
common ancestor; become variant due to
mutation
 Convergent evolution: no common
ancestor; become similar due to functional
or physical constraint
Anti-freeze protein: convergent
evolution

crystal.biochem.queensu.ca
Homologous fold

Ranganathan
 Analogous fold

Ranganathan
How well can we predict protein
structure from sequence now? and
design its function?
Why Can’t we?
Structure Prediction Methods

Homology modeling

Fold recognition

ab initio

0 10 20 30 40 50 60 70 80 90 100
% sequence identity
http://predictioncenter.gc.ucdavis.edu/casp7/Casp7.html
One lab dominated in CASP4
Science 2005
Science 2003
A computer-designed protein (93 aa)
with 1.2 A resolution
Protein Designer: Homme W. Hellinga (Duke)
Dwyer, MA, Looger, LL & Hellinga, HW (2004) Computational design of a
biologically active enzyme. Science, 304(5679):1967-1971. (Abstract)

Allert, M. Rizk, S Looger, LL & Hellinga, HW (2004) Computational design of

receptors for an organophosphate surrogate of the nerve agent soman. PNAS,
101(21):7907-7912. (Abstract)

Dwyer, MA, Looger, LL & Hellinga, HW (2003). Computational design of a Zn2+

receptor that controls bacterial gene expression. PNAS 100(20):11255-11260. (Abstract
)

Looger, LL, Dwyer, MW, Smith, JJ & Hellinga, HW (2003) Computational design of
receptor and sensor proteins with novel functions. Nature, 423:185-190. (Abstract)

Yang, W, Jones, LM, Isley, L, Ye, Y, Lee, H-W, Wilkins, A, Liu, ZR , Hellinga, HW,
Malchow, R, Ghazi, M & Yang, JJ (2003) Rational design of a calcium-binding protein.
J. Am. Chem. Soc., 125:6165-6171. (Abstract)
Beyond single structure
Methods for
determining
macro-
molecular
assembly
structure

Sali et al, 2003

Hybrid approach for solving macromolecular
complex structures

Sali et al, 2003

Science, 2004
Assignment
Write a report (3 pages maximum) on a recent (2005 or
2006) structure biology paper from Nature, Science, or
Cell (Do not pick from any other journal!). Be sure to use
your own words (i.e. copy texts from literature, if found,
will receive zero grade)!

Report should be submitted by Nov. 29, 2006.