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Article ; Online: How ligand binds to the type 1 insulin-like growth factor receptor

Yibin Xu / Geoffrey K.-W. Kong / John G. Menting / Mai B. Margetts / Carlie A. Delaine / Lauren M. Jenkin / Vladislav V. Kiselyov / Pierre De Meyts / Briony E. Forbes / Michael C. Lawrence

Nature Communications, Vol 9, Iss 1, Pp 1-

2018 Volume 13

Abstract: The human type 1 insulin-like growth factor receptor (IGF-1R) is important for normal human growth and development. Here, the authors present the crystal structures of the IGF-1R ectodomain both in its apo form and in complex with its ligand insulin-like ...

Abstract	The human type 1 insulin-like growth factor receptor (IGF-1R) is important for normal human growth and development. Here, the authors present the crystal structures of the IGF-1R ectodomain both in its apo form and in complex with its ligand insulin-like growth factor I and discuss the receptor activation mechanism.
Keywords	Science ; Q
Language	English
Publishing date	2018-02-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: How ligand binds to the type 1 insulin-like growth factor receptor

Yibin Xu / Geoffrey K.-W. Kong / John G. Menting / Mai B. Margetts / Carlie A. Delaine / Lauren M. Jenkin / Vladislav V. Kiselyov / Pierre De Meyts / Briony E. Forbes / Michael C. Lawrence

Nature Communications, Vol 9, Iss 1, Pp 1-

2018 Volume 13

Abstract	The human type 1 insulin-like growth factor receptor (IGF-1R) is important for normal human growth and development. Here, the authors present the crystal structures of the IGF-1R ectodomain both in its apo form and in complex with its ligand insulin-like growth factor I and discuss the receptor activation mechanism.
Keywords	Science ; Q
Language	English
Publishing date	2018-02-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: How ligand binds to the type 1 insulin-like growth factor receptor.

Xu, Yibin / Kong, Geoffrey K-W / Menting, John G / Margetts, Mai B / Delaine, Carlie A / Jenkin, Lauren M / Kiselyov, Vladislav V / De Meyts, Pierre / Forbes, Briony E / Lawrence, Michael C

Nature communications

2018 Volume 9, Issue 1, Page(s) 821

Abstract: Human type 1 insulin-like growth factor receptor is a homodimeric receptor tyrosine kinase that signals into pathways directing normal cellular growth, differentiation and proliferation, with aberrant signalling implicated in cancer. Insulin-like growth ... ...

Abstract	Human type 1 insulin-like growth factor receptor is a homodimeric receptor tyrosine kinase that signals into pathways directing normal cellular growth, differentiation and proliferation, with aberrant signalling implicated in cancer. Insulin-like growth factor binding is understood to relax conformational restraints within the homodimer, initiating transphosphorylation of the tyrosine kinase domains. However, no three-dimensional structures exist for the receptor ectodomain to inform atomic-level understanding of these events. Here, we present crystal structures of the ectodomain in apo form and in complex with insulin-like growth factor I, the latter obtained by crystal soaking. These structures not only provide a wealth of detail of the growth factor interaction with the receptor's primary ligand-binding site but also indicate that ligand binding separates receptor domains by a mechanism of induced fit. Our findings are of importance to the design of agents targeting IGF-1R and its partner protein, the human insulin receptor.
MeSH term(s)	Amino Acid Sequence ; Animals ; Binding Sites ; CHO Cells ; Cricetulus ; Crystallography, X-Ray ; Gene Expression ; Humans ; Insulin-Like Growth Factor I/chemistry ; Insulin-Like Growth Factor I/genetics ; Insulin-Like Growth Factor I/metabolism ; Kinetics ; Ligands ; Models, Molecular ; Mutation ; Protein Binding ; Protein Conformation, alpha-Helical ; Protein Conformation, beta-Strand ; Protein Interaction Domains and Motifs ; Receptors, Somatomedin/chemistry ; Receptors, Somatomedin/genetics ; Receptors, Somatomedin/metabolism ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Sf9 Cells ; Spodoptera
Chemical Substances	IGF1 protein, human ; IGF1R protein, human ; Ligands ; Receptors, Somatomedin ; Recombinant Proteins ; Insulin-Like Growth Factor I (67763-96-6)
Language	English
Publishing date	2018-02-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2041-1723
ISSN (online)	2041-1723
DOI	10.1038/s41467-018-03219-7
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Article ; Online: Structural Congruency of Ligand Binding to the Insulin and Insulin/Type 1 Insulin-like Growth Factor Hybrid Receptors.

Menting, John G / Lawrence, Callum F / Kong, Geoffrey K-W / Margetts, Mai B / Ward, Colin W / Lawrence, Michael C

Structure (London, England : 1993)

2015 Volume 23, Issue 7, Page(s) 1271–1282

Abstract: The homodimeric insulin and type 1 insulin-like growth factor receptors (IR and IGF-1R) share a common architecture and each can bind all three ligands within the family: insulin and insulin-like growth factors I and II (IGF-I and IFG-II). The receptor ... ...

Abstract	The homodimeric insulin and type 1 insulin-like growth factor receptors (IR and IGF-1R) share a common architecture and each can bind all three ligands within the family: insulin and insulin-like growth factors I and II (IGF-I and IFG-II). The receptor monomers also assemble as heterodimers, the primary ligand-binding sites of which each comprise the first leucine-rich repeat domain (L1) of one receptor type and an α-chain C-terminal segment (αCT) of the second receptor type. We present here crystal structures of IGF-I bound to such a hybrid primary binding site and of a ligand-free version of an IR αCT peptide bound to an IR L1 plus cysteine-rich domain construct (IR310.T). These structures, refined at 3.0-Å resolution, prove congruent to respective existing structures of insulin-complexed IR310.T and the intact apo-IR ectodomain. As such, they provide key missing links in the emerging, but sparse, repertoire of structures defining the receptor family.
MeSH term(s)	Binding Sites ; Crystallography, X-Ray ; Humans ; Insulin-Like Growth Factor I/chemistry ; Ligands ; Models, Molecular ; Protein Binding ; Protein Structure, Quaternary ; Protein Structure, Secondary ; Receptor, IGF Type 1/chemistry ; Receptor, Insulin/chemistry
Chemical Substances	Ligands ; Insulin-Like Growth Factor I (67763-96-6) ; Receptor, IGF Type 1 (EC 2.7.10.1) ; Receptor, Insulin (EC 2.7.10.1)
Language	English
Publishing date	2015-07-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1213087-4
ISSN	1878-4186 ; 0969-2126
ISSN (online)	1878-4186
ISSN	0969-2126
DOI	10.1016/j.str.2015.04.016
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Article ; Online: The first plant acyl-CoA-binding protein structures: the close homologues OsACBP1 and OsACBP2 from rice.

Guo, Ze Hua / Chan, Wallace H Y / Kong, Geoffrey K W / Hao, Quan / Chye, Mee Len

Acta crystallographica. Section D, Structural biology

2017 Volume 73, Issue Pt 5, Page(s) 438–448

Abstract: Acyl-CoA-binding proteins (ACBPs) are a family of proteins that facilitate the binding of long-chain acyl-CoA esters at a conserved acyl-CoA-binding domain. ACBPs act to form intracellular acyl-CoA pools, transport acyl-CoA esters and regulate lipid ... ...

Abstract	Acyl-CoA-binding proteins (ACBPs) are a family of proteins that facilitate the binding of long-chain acyl-CoA esters at a conserved acyl-CoA-binding domain. ACBPs act to form intracellular acyl-CoA pools, transport acyl-CoA esters and regulate lipid metabolism. In the model plant Arabidopsis thaliana, a family of six ACBPs has been demonstrated to function in stress and development. Six ACBPs (OsACBPs) have also been identified in Oryza sativa (rice), but they are not as well characterized as those in Arabidopsis thaliana. To understand the need in rice for the two 10 kDa ACBPs, namely OsACBP1 and OsACBP2, which share 79% sequence identity, their crystal structures were elucidated and their affinities toward acyl-CoA esters were compared using isothermal titration calorimetry. OsACBP2 was found to display a higher binding affinity for unsaturated acyl-CoA esters than OsACBP1. A difference between the two proteins is observed at helix 3 and is predicted to lead to different ligand-binding modes in terms of the shape of the binding pocket and the residues that are involved. OsACBP1 thus resembles bovine ACBP, while OsACBP2 is similar to human liver ACBP, in both structure and binding affinity. This is the first time that ACBP structures have been reported from plants, and suggests that OsACBP1 and OsACBP2 are not redundant in function despite their high sequence identity and general structural similarity.
MeSH term(s)	Acyl Coenzyme A/metabolism ; Amino Acid Sequence ; Animals ; Carrier Proteins/chemistry ; Carrier Proteins/metabolism ; Cattle ; Humans ; Models, Molecular ; Oryza/chemistry ; Oryza/metabolism ; Plant Proteins/chemistry ; Plant Proteins/metabolism ; Protein Binding ; Sequence Alignment ; X-Ray Diffraction
Chemical Substances	Acyl Coenzyme A ; Carrier Proteins ; Plant Proteins
Language	English
Publishing date	2017-05-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2020492-9
ISSN	2059-7983 ; 1399-0047 ; 0907-4449
ISSN (online)	2059-7983 ; 1399-0047
ISSN	0907-4449
DOI	10.1107/S2059798317004193
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Article ; Online: Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome.

Walitt, Brian / Singh, Komudi / LaMunion, Samuel R / Hallett, Mark / Jacobson, Steve / Chen, Kong / Enose-Akahata, Yoshimi / Apps, Richard / Barb, Jennifer J / Bedard, Patrick / Brychta, Robert J / Buckley, Ashura Williams / Burbelo, Peter D / Calco, Brice / Cathay, Brianna / Chen, Li / Chigurupati, Snigdha / Chen, Jinguo / Cheung, Foo /

Chin, Lisa M K / Coleman, Benjamin W / Courville, Amber B / Deming, Madeleine S / Drinkard, Bart / Feng, Li Rebekah / Ferrucci, Luigi / Gabel, Scott A / Gavin, Angelique / Goldstein, David S / Hassanzadeh, Shahin / Horan, Sean C / Horovitz, Silvina G / Johnson, Kory R / Govan, Anita Jones / Knutson, Kristine M / Kreskow, Joy D / Levin, Mark / Lyons, Jonathan J / Madian, Nicholas / Malik, Nasir / Mammen, Andrew L / McCulloch, John A / McGurrin, Patrick M / Milner, Joshua D / Moaddel, Ruin / Mueller, Geoffrey A / Mukherjee, Amrita / Muñoz-Braceras, Sandra / Norato, Gina / Pak, Katherine / Pinal-Fernandez, Iago / Popa, Traian / Reoma, Lauren B / Sack, Michael N / Safavi, Farinaz / Saligan, Leorey N / Sellers, Brian A / Sinclair, Stephen / Smith, Bryan / Snow, Joseph / Solin, Stacey / Stussman, Barbara J / Trinchieri, Giorgio / Turner, Sara A / Vetter, C Stephenie / Vial, Felipe / Vizioli, Carlotta / Williams, Ashley / Yang, Shanna B / Nath, Avindra

Nature communications

2024 Volume 15, Issue 1, Page(s) 907

Abstract: Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined, the pathophysiology is unknown, and no disease-modifying treatments are available. We used rigorous ... ...

Abstract	Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined, the pathophysiology is unknown, and no disease-modifying treatments are available. We used rigorous criteria to recruit PI-ME/CFS participants with matched controls to conduct deep phenotyping. Among the many physical and cognitive complaints, one defining feature of PI-ME/CFS was an alteration of effort preference, rather than physical or central fatigue, due to dysfunction of integrative brain regions potentially associated with central catechol pathway dysregulation, with consequences on autonomic functioning and physical conditioning. Immune profiling suggested chronic antigenic stimulation with increase in naïve and decrease in switched memory B-cells. Alterations in gene expression profiles of peripheral blood mononuclear cells and metabolic pathways were consistent with cellular phenotypic studies and demonstrated differences according to sex. Together these clinical abnormalities and biomarker differences provide unique insight into the underlying pathophysiology of PI-ME/CFS, which may guide future intervention.
MeSH term(s)	Humans ; Fatigue Syndrome, Chronic/metabolism ; Leukocytes, Mononuclear/metabolism ; Communicable Diseases/metabolism ; Biomarkers/metabolism ; Phenotype
Chemical Substances	Biomarkers
Language	English
Publishing date	2024-02-21
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-45107-3
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Article ; Online: Topographic Mapping of the Synaptic Cleft into Adhesive Nanodomains.

Perez de Arce, Karen / Schrod, Nikolas / Metzbower, Sarah W R / Allgeyer, Edward / Kong, Geoffrey K-W / Tang, Ai-Hui / Krupp, Alexander J / Stein, Valentin / Liu, Xinran / Bewersdorf, Jörg / Blanpied, Thomas A / Lucić, Vladan / Biederer, Thomas

Neuron

2015 Volume 88, Issue 6, Page(s) 1165–1172

Abstract: The cleft is an integral part of synapses, yet its macromolecular organization remains unclear. We show here that the cleft of excitatory synapses exhibits a distinct density profile as measured by cryoelectron tomography (cryo-ET). Aiming for molecular ... ...

Abstract	The cleft is an integral part of synapses, yet its macromolecular organization remains unclear. We show here that the cleft of excitatory synapses exhibits a distinct density profile as measured by cryoelectron tomography (cryo-ET). Aiming for molecular insights, we analyzed the synapse-organizing proteins Synaptic Cell Adhesion Molecule 1 (SynCAM 1) and EphB2. Cryo-ET of SynCAM 1 knockout and overexpressor synapses showed that this immunoglobulin protein shapes the cleft's edge. SynCAM 1 delineates the postsynaptic perimeter as determined by immunoelectron microscopy and super-resolution imaging. In contrast, the EphB2 receptor tyrosine kinase is enriched deeper within the postsynaptic area. Unexpectedly, SynCAM 1 can form ensembles proximal to postsynaptic densities, and synapses containing these ensembles were larger. Postsynaptic SynCAM 1 surface puncta were not static but became enlarged after a long-term depression paradigm. These results support that the synaptic cleft is organized on a nanoscale into sub-compartments marked by distinct trans-synaptic complexes.
MeSH term(s)	Animals ; Cell Adhesion Molecule-1 ; Cell Adhesion Molecules/physiology ; Cell Adhesion Molecules/ultrastructure ; Cell Adhesion Molecules, Neuronal/physiology ; Cell Adhesion Molecules, Neuronal/ultrastructure ; Cells, Cultured ; Hippocampus/physiology ; Hippocampus/ultrastructure ; Immunoglobulins/physiology ; Immunoglobulins/ultrastructure ; Male ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Microscopy, Immunoelectron ; Neurons/physiology ; Neurons/ultrastructure ; Synapses/physiology ; Synapses/ultrastructure
Chemical Substances	Cadm1 protein, mouse ; Cell Adhesion Molecule-1 ; Cell Adhesion Molecules ; Cell Adhesion Molecules, Neuronal ; Immunoglobulins
Language	English
Publishing date	2015-12-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	808167-0
ISSN	1097-4199 ; 0896-6273
ISSN (online)	1097-4199
ISSN	0896-6273
DOI	10.1016/j.neuron.2015.11.011
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Article ; Online: SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness.

Corbett, Kizzmekia S / Edwards, Darin K / Leist, Sarah R / Abiona, Olubukola M / Boyoglu-Barnum, Seyhan / Gillespie, Rebecca A / Himansu, Sunny / Schäfer, Alexandra / Ziwawo, Cynthia T / DiPiazza, Anthony T / Dinnon, Kenneth H / Elbashir, Sayda M / Shaw, Christine A / Woods, Angela / Fritch, Ethan J / Martinez, David R / Bock, Kevin W / Minai, Mahnaz / Nagata, Bianca M /

Hutchinson, Geoffrey B / Wu, Kai / Henry, Carole / Bahl, Kapil / Garcia-Dominguez, Dario / Ma, LingZhi / Renzi, Isabella / Kong, Wing-Pui / Schmidt, Stephen D / Wang, Lingshu / Zhang, Yi / Phung, Emily / Chang, Lauren A / Loomis, Rebecca J / Altaras, Nedim Emil / Narayanan, Elisabeth / Metkar, Mihir / Presnyak, Vlad / Liu, Cuiping / Louder, Mark K / Shi, Wei / Leung, Kwanyee / Yang, Eun Sung / West, Ande / Gully, Kendra L / Stevens, Laura J / Wang, Nianshuang / Wrapp, Daniel / Doria-Rose, Nicole A / Stewart-Jones, Guillaume / Bennett, Hamilton / Alvarado, Gabriela S / Nason, Martha C / Ruckwardt, Tracy J / McLellan, Jason S / Denison, Mark R / Chappell, James D / Moore, Ian N / Morabito, Kaitlyn M / Mascola, John R / Baric, Ralph S / Carfi, Andrea / Graham, Barney S

Nature

2020 Volume 586, Issue 7830, Page(s) 567–571

Abstract: A vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is needed to control the coronavirus disease 2019 (COVID-19) global pandemic. Structural studies have led to the development of mutations that stabilize Betacoronavirus spike ... ...

Abstract	A vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is needed to control the coronavirus disease 2019 (COVID-19) global pandemic. Structural studies have led to the development of mutations that stabilize Betacoronavirus spike proteins in the prefusion state, improving their expression and increasing immunogenicity
MeSH term(s)	Animals ; Antibodies, Neutralizing/immunology ; Betacoronavirus/genetics ; Betacoronavirus/immunology ; CD8-Positive T-Lymphocytes/immunology ; COVID-19 ; COVID-19 Vaccines ; Clinical Trials, Phase III as Topic ; Coronavirus Infections/genetics ; Coronavirus Infections/immunology ; Coronavirus Infections/prevention & control ; Coronavirus Infections/virology ; Female ; Lung/immunology ; Lung/virology ; Mice ; Mutation ; Nose/immunology ; Nose/virology ; Pandemics/prevention & control ; Pneumonia, Viral/immunology ; Pneumonia, Viral/prevention & control ; Pneumonia, Viral/virology ; RNA, Messenger/genetics ; RNA, Viral/genetics ; SARS-CoV-2 ; Th1 Cells/immunology ; Toll-Like Receptor 4/agonists ; Toll-Like Receptor 4/immunology ; Viral Vaccines/chemistry ; Viral Vaccines/genetics ; Viral Vaccines/immunology
Chemical Substances	Antibodies, Neutralizing ; COVID-19 Vaccines ; RNA, Messenger ; RNA, Viral ; Tlr4 protein, mouse ; Toll-Like Receptor 4 ; Viral Vaccines ; mRNA-1273 vaccine (EPK39PL4R4)
Keywords	covid19
Language	English
Publishing date	2020-08-05
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-020-2622-0
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Article: SARS-CoV-2 mRNA Vaccine Development Enabled by Prototype Pathogen Preparedness.

Corbett, Kizzmekia S / Edwards, Darin / Leist, Sarah R / Abiona, Olubukola M / Boyoglu-Barnum, Seyhan / Gillespie, Rebecca A / Himansu, Sunny / Schäfer, Alexandra / Ziwawo, Cynthia T / DiPiazza, Anthony T / Dinnon, Kenneth H / Elbashir, Sayda M / Shaw, Christine A / Woods, Angela / Fritch, Ethan J / Martinez, David R / Bock, Kevin W / Minai, Mahnaz / Nagata, Bianca M /

Hutchinson, Geoffrey B / Bahl, Kapil / Garcia-Dominguez, Dario / Ma, LingZhi / Renzi, Isabella / Kong, Wing-Pui / Schmidt, Stephen D / Wang, Lingshu / Zhang, Yi / Stevens, Laura J / Phung, Emily / Chang, Lauren A / Loomis, Rebecca J / Altaras, Nedim Emil / Narayanan, Elisabeth / Metkar, Mihir / Presnyak, Vlad / Liu, Catherine / Louder, Mark K / Shi, Wei / Leung, Kwanyee / Yang, Eun Sung / West, Ande / Gully, Kendra L / Wang, Nianshuang / Wrapp, Daniel / Doria-Rose, Nicole A / Stewart-Jones, Guillaume / Bennett, Hamilton / Nason, Martha C / Ruckwardt, Tracy J / McLellan, Jason S / Denison, Mark R / Chappell, James D / Moore, Ian N / Morabito, Kaitlyn M / Mascola, John R / Baric, Ralph S / Carfi, Andrea / Graham, Barney S

bioRxiv : the preprint server for biology

2020

Abstract: A SARS-CoV-2 vaccine is needed to control the global COVID-19 public health crisis. Atomic-level structures directed the application of prefusion-stabilizing mutations that improved expression and immunogenicity of betacoronavirus spike proteins. Using ... ...

Abstract	A SARS-CoV-2 vaccine is needed to control the global COVID-19 public health crisis. Atomic-level structures directed the application of prefusion-stabilizing mutations that improved expression and immunogenicity of betacoronavirus spike proteins. Using this established immunogen design, the release of SARS-CoV-2 sequences triggered immediate rapid manufacturing of an mRNA vaccine expressing the prefusion-stabilized SARS-CoV-2 spike trimer (mRNA-1273). Here, we show that mRNA-1273 induces both potent neutralizing antibody and CD8 T cell responses and protects against SARS-CoV-2 infection in lungs and noses of mice without evidence of immunopathology. mRNA-1273 is currently in a Phase 2 clinical trial with a trajectory towards Phase 3 efficacy evaluation.
Keywords	covid19
Language	English
Publishing date	2020-06-11
Publishing country	United States
Document type	Preprint
DOI	10.1101/2020.06.11.145920
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Article ; Online: How insulin engages its primary binding site on the insulin receptor.

Menting, John G / Whittaker, Jonathan / Margetts, Mai B / Whittaker, Linda J / Kong, Geoffrey K-W / Smith, Brian J / Watson, Christopher J / Záková, Lenka / Kletvíková, Emília / Jiráček, Jiří / Chan, Shu Jin / Steiner, Donald F / Dodson, Guy G / Brzozowski, Andrzej M / Weiss, Michael A / Ward, Colin W / Lawrence, Michael C

Nature

2013 Volume 493, Issue 7431, Page(s) 241–245

Abstract: Insulin receptor signalling has a central role in mammalian biology, regulating cellular metabolism, growth, division, differentiation and survival. Insulin resistance contributes to the pathogenesis of type 2 diabetes mellitus and the onset of Alzheimer' ...

Abstract	Insulin receptor signalling has a central role in mammalian biology, regulating cellular metabolism, growth, division, differentiation and survival. Insulin resistance contributes to the pathogenesis of type 2 diabetes mellitus and the onset of Alzheimer's disease; aberrant signalling occurs in diverse cancers, exacerbated by cross-talk with the homologous type 1 insulin-like growth factor receptor (IGF1R). Despite more than three decades of investigation, the three-dimensional structure of the insulin-insulin receptor complex has proved elusive, confounded by the complexity of producing the receptor protein. Here we present the first view, to our knowledge, of the interaction of insulin with its primary binding site on the insulin receptor, on the basis of four crystal structures of insulin bound to truncated insulin receptor constructs. The direct interaction of insulin with the first leucine-rich-repeat domain (L1) of insulin receptor is seen to be sparse, the hormone instead engaging the insulin receptor carboxy-terminal α-chain (αCT) segment, which is itself remodelled on the face of L1 upon insulin binding. Contact between insulin and L1 is restricted to insulin B-chain residues. The αCT segment displaces the B-chain C-terminal β-strand away from the hormone core, revealing the mechanism of a long-proposed conformational switch in insulin upon receptor engagement. This mode of hormone-receptor recognition is novel within the broader family of receptor tyrosine kinases. We support these findings by photo-crosslinking data that place the suggested interactions into the context of the holoreceptor and by isothermal titration calorimetry data that dissect the hormone-insulin receptor interface. Together, our findings provide an explanation for a wealth of biochemical data from the insulin receptor and IGF1R systems relevant to the design of therapeutic insulin analogues.
MeSH term(s)	Animals ; Binding Sites ; Calorimetry ; Cattle ; Cell Line ; Crystallography, X-Ray ; Humans ; Insulin/chemistry ; Insulin/metabolism ; Leucine/metabolism ; Ligands ; Models, Molecular ; Protein Binding ; Protein Structure, Secondary ; Receptor, Insulin/chemistry ; Receptor, Insulin/metabolism ; Reproducibility of Results
Chemical Substances	Insulin ; Ligands ; Receptor, Insulin (EC 2.7.10.1) ; Leucine (GMW67QNF9C)
Language	English
Publishing date	2013-01-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/nature11781
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