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* Residue conservation analysis
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PDB id:
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Hormone
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Title:
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Human insulin two disulfide model, nmr, 10 structures
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Structure:
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Insulin. Chain: a. Engineered: yes. Mutation: yes. Insulin. Chain: b. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Organ: pancreas. Organ: pancreas
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NMR struc:
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10 models
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Authors:
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Q.X.Hua,S.Q.Hu,B.H.Frank,W.H.Jia,Y.C.Chu,S.H.Wang,G.T.Burke, P.G.Katsoyannis,M.A.Weiss
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Key ref:
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Q.X.Hua
et al.
(1996).
Mapping the functional surface of insulin by design: structure and function of a novel A-chain analogue.
J Mol Biol,
264,
390-403.
PubMed id:
DOI:
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Date:
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14-Oct-96
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Release date:
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01-Apr-97
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PROCHECK
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Headers
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References
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DOI no:
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J Mol Biol
264:390-403
(1996)
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PubMed id:
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Mapping the functional surface of insulin by design: structure and function of a novel A-chain analogue.
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Q.X.Hua,
S.Q.Hu,
B.H.Frank,
W.Jia,
Y.C.Chu,
S.H.Wang,
G.T.Burke,
P.G.Katsoyannis,
M.A.Weiss.
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ABSTRACT
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Functional surfaces of a protein are often mapped by combination of X-ray
crystallography and mutagenesis. Such studies of insulin have yielded
paradoxical results, suggesting that the native state is inactive and
reorganizes on receptor binding. Of particular interest is the N-terminal
alpha-helix of the A-chain. Does this segment function as an alpha-helix or
reorganize as recently proposed in a prohormone-convertase complex? To correlate
structure and function, we describe a mapping strategy based on protein design.
The solution structure of an engineered monomer ([AspB10, LysB28, ProB29]-human
insulin) is determined at neutral pH as a template for synthesis of a novel
A-chain analogue. Designed by analogy to a protein-folding intermediate, the
analogue lacks the A6-A11 disulphide bridge; the cysteine residues are replaced
by serine. Its solution structure is remarkable for segmental unfolding of the
N-terminal A-chain alpha-helix (A1 to A8) in an otherwise native subdomain. The
structure demonstrates that the overall orientation of the A and B chains is
consistent with reorganization of the A-chain's N-terminal segment.
Nevertheless, the analogue's low biological activity suggests that this segment,
a site of clinical mutation causing diabetes mellitus, functions as a preformed
recognition alpha-helix.
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Selected figure(s)
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Figure 2.
Figure 2. A, Ribbon model of T6 insulin hexamer in 2-Zn crystal form (Protein Data Bank identifier 2ZN; Baker et al.,
1988). Protomers are shown in red and green. The central Zn-binding sites are coordinated by HisB10 (white). The
view is along the 3-fold symmetry axis of the hexamer. B, Surface representation of T-state protomer (2-Zn molecule 1)
showing residues HisB10, ProB28 and LysB29 (green; sites of mutation in DKP-insulin) and cystine A6--A11 (yellow;
sites of serine substitution in DKP-[A6-A11]
Ser
). Because the latter is inaccessible, the yellow surface is not well seen.
The view is rotated from that shown in A to visualize most clearly the relevant protein surfaces. C, Stereo depiction
of internal environment of A6--A11 disulphide bridge (yellow) in 2-Zn molecule 1; neighbouring aliphatic side-chains
are shown in red (A-chain) and blue (B-chain) as indicated.
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Figure 5.
Figure 5. Differences in
1
H-NMR chemical shifts
between DKP-insulin and DKP-[A6-A11]
Ser
at neutral pH
are shown by residue: a, amide resonances, b, a
resonances, c, b methylene resonances, and d, other
side-chain resonances. For each residue only the
difference largest in magnitude is shown. A-chain
residues are numbered 1 to 21; B-chain residues, 22 to 51.
Arrows indicate sites of serine substitution in DKP-[A6-
A11]
Ser
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(1996,
264,
390-403)
copyright 1996.
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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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M.Liu,
L.Haataja,
J.Wright,
N.P.Wickramasinghe,
Q.X.Hua,
N.F.Phillips,
F.Barbetti,
M.A.Weiss,
and
P.Arvan
(2010).
Mutant INS-gene induced diabetes of youth: proinsulin cysteine residues impose dominant-negative inhibition on wild-type proinsulin transport.
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PLoS One,
5,
e13333.
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Y.Yang,
Q.X.Hua,
J.Liu,
E.H.Shimizu,
M.H.Choquette,
R.B.Mackin,
and
M.A.Weiss
(2010).
Solution structure of proinsulin: connecting domain flexibility and prohormone processing.
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J Biol Chem,
285,
7847-7851.
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PDB code:
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Z.Ganim,
K.C.Jones,
and
A.Tokmakoff
(2010).
Insulin dimer dissociation and unfolding revealed by amide I two-dimensional infrared spectroscopy.
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Phys Chem Chem Phys,
12,
3579-3588.
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B.Xu,
K.Huang,
Y.C.Chu,
S.Q.Hu,
S.Nakagawa,
S.Wang,
R.Y.Wang,
J.Whittaker,
P.G.Katsoyannis,
and
M.A.Weiss
(2009).
Decoding the Cryptic Active Conformation of a Protein by Synthetic Photoscanning: INSULIN INSERTS A DETACHABLE ARM BETWEEN RECEPTOR DOMAINS.
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J Biol Chem,
284,
14597-14608.
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G.Le Flem,
J.Pecher,
V.Le Flem-Bonhomme,
A.Withdrawn,
J.Rochette,
J.P.Pujol,
and
P.Bogdanowicz
(2009).
Human insulin A-chain peptide analog(s) with in vitro biological activity.
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Cell Biochem Funct,
27,
370-377.
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M.A.Weiss
(2009).
Proinsulin and the genetics of diabetes mellitus.
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J Biol Chem,
284,
19159-19163.
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M.Liu,
Z.L.Wan,
Y.C.Chu,
H.Aladdin,
B.Klaproth,
M.Choquette,
Q.X.Hua,
R.B.Mackin,
J.S.Rao,
P.De Meyts,
P.G.Katsoyannis,
P.Arvan,
and
M.A.Weiss
(2009).
Crystal structure of a "nonfoldable" insulin: impaired folding efficiency despite native activity.
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J Biol Chem,
284,
35259-35272.
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PDB code:
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Q.X.Hua,
B.Xu,
K.Huang,
S.Q.Hu,
S.Nakagawa,
W.Jia,
S.Wang,
J.Whittaker,
P.G.Katsoyannis,
and
M.A.Weiss
(2009).
Enhancing the Activity of a Protein by Stereospecific Unfolding: CONFORMATIONAL LIFE CYCLE OF INSULIN AND ITS EVOLUTIONARY ORIGINS.
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J Biol Chem,
284,
14586-14596.
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PDB codes:
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Q.X.Hua,
S.H.Nakagawa,
W.Jia,
K.Huang,
N.B.Phillips,
S.Q.Hu,
and
M.A.Weiss
(2008).
Design of an active ultrastable single-chain insulin analog: synthesis, structure, and therapeutic implications.
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J Biol Chem,
283,
14703-14716.
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PDB codes:
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Z.L.Wan,
K.Huang,
S.Q.Hu,
J.Whittaker,
and
M.A.Weiss
(2008).
The structure of a mutant insulin uncouples receptor binding from protein allostery. An electrostatic block to the TR transition.
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J Biol Chem,
283,
21198-21210.
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Z.Y.Guo,
Z.S.Qiao,
and
Y.M.Feng
(2008).
The in vitro oxidative folding of the insulin superfamily.
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Antioxid Redox Signal,
10,
127-140.
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J.P.Mayer,
F.Zhang,
and
R.D.DiMarchi
(2007).
Insulin structure and function.
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Biopolymers,
88,
687-713.
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K.Huang,
S.J.Chan,
Q.X.Hua,
Y.C.Chu,
R.Y.Wang,
B.Klaproth,
W.Jia,
J.Whittaker,
P.De Meyts,
S.H.Nakagawa,
D.F.Steiner,
P.G.Katsoyannis,
and
M.A.Weiss
(2007).
The A-chain of insulin contacts the insert domain of the insulin receptor. Photo-cross-linking and mutagenesis of a diabetes-related crevice.
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J Biol Chem,
282,
35337-35349.
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PDB codes:
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M.Koch,
F.F.Schmid,
V.Zoete,
and
M.Meuwly
(2006).
Insulin: a model system for nanomedicine?
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Nanomed,
1,
373-378.
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Q.X.Hua,
J.P.Mayer,
W.Jia,
J.Zhang,
and
M.A.Weiss
(2006).
The folding nucleus of the insulin superfamily: a flexible peptide model foreshadows the native state.
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J Biol Chem,
281,
28131-28142.
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Q.X.Hua,
M.Liu,
S.Q.Hu,
W.Jia,
P.Arvan,
and
M.A.Weiss
(2006).
A conserved histidine in insulin is required for the foldability of human proinsulin: structure and function of an ALAB5 analog.
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J Biol Chem,
281,
24889-24899.
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PDB code:
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Q.X.Hua,
S.Nakagawa,
S.Q.Hu,
W.Jia,
S.Wang,
and
M.A.Weiss
(2006).
Toward the active conformation of insulin: stereospecific modulation of a structural switch in the B chain.
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J Biol Chem,
281,
24900-24909.
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PDB codes:
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S.H.Nakagawa,
Q.X.Hua,
S.Q.Hu,
W.Jia,
S.Wang,
P.G.Katsoyannis,
and
M.A.Weiss
(2006).
Chiral mutagenesis of insulin. Contribution of the B20-B23 beta-turn to activity and stability.
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J Biol Chem,
281,
22386-22396.
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J.Jing,
and
S.Lu
(2005).
Inhibition of platelet aggregation of a mutant proinsulin chimera engineered by introduction of a native Lys-Gly-Asp-containing sequence.
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Biotechnol Lett,
27,
1259-1265.
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V.Zoete,
M.Meuwly,
and
M.Karplus
(2005).
Study of the insulin dimerization: binding free energy calculations and per-residue free energy decomposition.
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Proteins,
61,
79-93.
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Q.X.Hua,
and
M.A.Weiss
(2004).
Mechanism of insulin fibrillation: the structure of insulin under amyloidogenic conditions resembles a protein-folding intermediate.
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J Biol Chem,
279,
21449-21460.
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PDB code:
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Y.Chen,
R.Jin,
H.Y.Dong,
and
Y.M.Feng
(2004).
In vitro refolding/unfolding pathways of amphioxus insulin-like peptide: implications for folding behavior of insulin family proteins.
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J Biol Chem,
279,
55224-55233.
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G.D.Smith,
and
R.H.Blessing
(2003).
Lessons from an aged, dried crystal of T(6) human insulin.
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Acta Crystallogr D Biol Crystallogr,
59,
1384-1394.
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PDB codes:
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Q.X.Hua,
S.H.Nakagawa,
J.Wilken,
R.R.Ramos,
W.Jia,
J.Bass,
and
M.A.Weiss
(2003).
A divergent INS protein in Caenorhabditis elegans structurally resembles human insulin and activates the human insulin receptor.
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Genes Dev,
17,
826-831.
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X.Y.Jia,
Z.Y.Guo,
Y.Wang,
Y.Xu,
S.S.Duan,
and
Y.M.Feng
(2003).
Peptide models of four possible insulin folding intermediates with two disulfides.
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Protein Sci,
12,
2412-2419.
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Z.L.Wan,
B.Xu,
Y.C.Chu,
P.G.Katsoyannis,
and
M.A.Weiss
(2003).
Crystal structure of allo-Ile(A2)-insulin, an inactive chiral analogue: implications for the mechanism of receptor binding.
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Biochemistry,
42,
12770-12783.
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PDB codes:
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Z.S.Qiao,
C.Y.Min,
Q.X.Hua,
M.A.Weiss,
and
Y.M.Feng
(2003).
In vitro refolding of human proinsulin. Kinetic intermediates, putative disulfide-forming pathway folding initiation site, and potential role of C-peptide in folding process.
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J Biol Chem,
278,
17800-17809.
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B.Xu,
Q.X.Hua,
S.H.Nakagawa,
W.Jia,
Y.C.Chu,
P.G.Katsoyannis,
and
M.A.Weiss
(2002).
A cavity-forming mutation in insulin induces segmental unfolding of a surrounding alpha-helix.
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Protein Sci,
11,
104-116.
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PDB code:
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Q.X.Hua,
Y.C.Chu,
W.Jia,
N.F.Phillips,
R.Y.Wang,
P.G.Katsoyannis,
and
M.A.Weiss
(2002).
Mechanism of insulin chain combination. Asymmetric roles of A-chain alpha-helices in disulfide pairing.
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J Biol Chem,
277,
43443-43453.
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PDB code:
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Z.Y.Guo,
L.Shen,
W.Gu,
A.Z.Wu,
J.G.Ma,
and
Y.M.Feng
(2002).
In vitro evolution of amphioxus insulin-like peptide to mammalian insulin.
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Biochemistry,
41,
10603-10607.
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Z.Y.Guo,
L.Shen,
and
Y.M.Feng
(2002).
The different folding behavior of insulin and insulin-like growth factor 1 is mainly controlled by their B-chain/domain.
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Biochemistry,
41,
1556-1567.
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Z.Y.Guo,
L.Shen,
and
Y.M.Feng
(2002).
The different energetic state of the intra A-chain/domain disulfide of insulin and insulin-like growth factor 1 is mainly controlled by their B-chain/domain.
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Biochemistry,
41,
10585-10592.
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M.A.Weiss,
Q.X.Hua,
W.Jia,
S.H.Nakagawa,
Y.C.Chu,
S.Q.Hu,
and
P.G.Katsoyannis
(2001).
Activities of monomeric insulin analogs at position A8 are uncorrelated with their thermodynamic stabilities.
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J Biol Chem,
276,
40018-40024.
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M.A.Weiss,
Q.X.Hua,
W.Jia,
Y.C.Chu,
R.Y.Wang,
and
P.G.Katsoyannis
(2000).
Hierarchical protein "un-design": insulin's intrachain disulfide bridge tethers a recognition alpha-helix.
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Biochemistry,
39,
15429-15440.
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Q.X.Hua,
W.H.Jia,
B.P.Bullock,
J.F.Habener,
and
M.A.Weiss
(1998).
Transcriptional activator-coactivator recognition: nascent folding of a kinase-inducible transactivation domain predicts its structure on coactivator binding.
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Biochemistry,
37,
5858-5866.
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C.McInnes,
and
B.D.Sykes
(1997).
Growth factor receptors: structure, mechanism, and drug discovery.
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Biopolymers,
43,
339-366.
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I.Pittman,
S.H.Nakagawa,
H.S.Tager,
and
D.F.Steiner
(1997).
Maintenance of the B-chain beta-turn in [GlyB24] insulin mutants: a steady-state fluorescence anisotropy study.
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Biochemistry,
36,
3430-3437.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
code is
shown on the right.
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Links
