Abstract
The structure–function paradigm, i.e. the concept that it is the three-dimensional structure of a protein that determines its function, has been partially modified by the discovery that a significant portion of the eukaryotic proteome is disordered and that this disorder is often functional. The presence of disorder is the origin of several issues, but the most relevant, at least from the biomedical point of view, is the difficulty of designing drugs in absence of a well-defined conformation of the target. To make the problem worse, we have to consider that often the disorder concerns proteins involved in diseases very relevant for human health, as cancer or neurodegenerative disorders. This review tries to summarize the state of the art of our knowledge on the subject and to describe the tools used to detect disorder and how drug design techniques used for well-folded proteins have been adjusted to this more challenging situation.
Abbreviations: AD: Alzheimer’s disease; CAID: Critical assessment of intrinsic protein disorder; CASP: Critical assessment of protein structure prediction; CD: circular dichroism; Cryo-EM: cryo-electron microscopy; DIBS: differential binding score; FRET: Förster resonance energy transfer; HD: Huntington’s disease; IDR: Intrinsically disordered regions; IDP: intrinsically disordered proteins; LDR: long intrinsically disordered regions; MG: Molten globule; MoRF: Molecular recognition feature; NMR: Nuclear magnetic resonance; PDB: Protein Data Bank; PD: Parkinson’s disease; POMS: polyoxometalates; SAXS: Small-angle X-ray scattering; SLiMS: short linear motifs; TFs: Transcription factors.
Acknowledgements
This paper is not founded by a specific grant, but I have to express my gratitude to all brilliant students and people that collaborated with me during my long scientific career. They cannot be listed here, otherwise these acknowledgments would be longer than the paper itself.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Subject Index
active-site directed regulation 59
Aβ42 65
Aducanumab 65
Afatinib 63
Allosteric mechanism 58
AlphaFold 55, 56, 62
Alzheimer’s disease (AD) 63
amyotrophic lateral sclerosis 63
α-synuclein 64
B factors 52, 53
β-catenin 62, 63
BMRB 55
CASP 56
CAID 56
chameleonic sequences 49
Charcot–Marie–Tooth diseases 63
c-MYC 63
circular dichroism spectroscopy (CD) 54
Condensate 60
conformational flexibility 50
Cryo-electron microscopy (cryo-EM) 55
denatured state 49
DIBS 54
disorder-to-order transition 51, 58
DisProt 53
DisResClusteredDB 53
dynamic behaviour 50
ELIXIR 54
ELM 54
eukaryotic protein 49, 52
flexible or disordered regions 52, 55
flexibility 49, 50, 52, 63, 65
FLIPPER 53
frontotemporal dementia 63
FRET 54, 55, 56
fully folded structure 49
FuzDB 54
High specificity 57
hydrophobic residues 52
hydrophilic surface 52
hydrodynamic radius 52
Huntington’s disease (HD) 63
Ibrutinib 63
IDEAL 53
In silico design 60
interdomain allostery 58
intramolecular regulation 58
intrinsically disordered proteins 50, 51
intrinsically disordered regions 51, 53
Lewy bodies 64
long intrinsically disordered regions 53
Low affinity 61
MAX 62, 63
metamorphic states 49
MFIB 54
missing residues 52, 54
mitochondrial myopathy 63
MobiDB 53
molten globule state 49
moonlighting proteins 49
MoonProt 55
MOREs 59
MORFs 59
morpheeins 49
NMR 51, 54, 55, 56, 59
on-off mechanism 50
Parkinson’s disease (PD) 63
PDB 49, 50, 51, 52
PED 54
phosphorylation site 50
Phosphotyrosine 62
phyla 50
PolyX, polyXY 57
post-translational modifications 52
pre-molten globule state 49
prion like 64
protein-DNA complexes 59
protein complexes 53
Prothymosin- α 58
random coil 49
Random conformation 49, 50
Sar1-GTP 53
Sec23/2 53
Sec13/31 53
signalling conduit function 59
single crystal electron diffraction 55
SH2B1 60
SLiMS 58
Small-angle X-ray scattering (SAXS) 54, 56
spinal muscular atrophy 63
STAT3 61
structure–function relationship 49
structural heterogeneity 52
TATA-binding protein 60
TBP-associated factors 60
Tcf 63
TFIID 60
TFs 61, 63
thermal parameters 52
unfolded 49, 50, 51, 60
UniProtKB 54
vibrational Raman optical activity 56
Wnt signalling pathway 63
X-ray powder diffraction 55
Additional information
Notes on contributors
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Giuseppe Zanotti
Giuseppe Zanotti was Full Professor of chemistry and then of Biochemistry at the University of Padova, Italy, before his retirement in October 2021. Since the beginning of his scientific career, he has been active in the field of structural biology, mostly using X-ray diffraction and, more recently, cryo-Electron Microscopy. He has been interested in proteins that bind and transport small hydrophobic molecules, of protein kinase CK2/inhibitor complexes and of proteins from pathogenic bacteria, in particular Helicobacter pylori. More recently he moved to the structure of filamentous viruses and protein complexes by cryo-EM. He has also been interested in theoretical aspects of macromolecular structures and has proposed the use of tensegrity as a unifying concept of protein folds. More information at the Blog https://sofiaelamela.com.