The insulin and insulin-like growth factor (IGF) system regulates essential biological functions such as growth, metabolism, and development. While its physiological roles are well characterized, the evolutionary origins and molecular diversification of its ligands and receptors remain incompletely defined. Here, we present the most comprehensive phylogenetic and sequence conservation analysis of this system to date, using over 1,000 sequences from vertebrates, invertebrates, and viruses. Our analyses reveal that insulin, IGF-1, and IGF-2 form distinct monophyletic clades that diverged after the emergence of vertebrates, with IGF-1 being the most conserved ligand. We show that IGF1R-binding residues, especially in the A- and B-domains of IGF-1, are highly conserved across vertebrates, while insulin's Site 2 residues, which overlap with its dimerization and hexamerization surface, are more variable-correlating with the loss of hexamer formation in hystricomorphs, reptiles, and jawless fish. Unexpectedly, we identify a 12-amino acid insert in the insulin receptor (IR) of turtles and tortoises, previously thought to be unique to mammalian IR-B isoform, challenging the view that receptor isoform diversity is a mammalian innovation. We also show that marsupials and monotremes retain ancestral receptor domain features shared with reptiles and birds and that avian insulins, particularly A-chain residues, are unusually conserved. Viral insulin/IGF-like peptides fall into two distinct clades that resemble either IGFs or insulin. Together, these findings illuminate the evolutionary architecture of the insulin/IGF system, highlight unexpected lineage-specific adaptations, and provide a framework for understanding hormone-receptor function across biology and therapeutic design.

Biology Department Boston College Chestnut Hill MA USA

Chemistry and Biology of Insulin and Insulin like Growth Factors Institute of Organic Chemistry and Biochemistry of the CAS Prague Czech Republic

Department of Cell Signalling de Duve Institute Catholic University of Louvain Brussels Belgium

Zobrazit více v PubMed

Alberini  CM. IGF2 in memory, neurodevelopmental disorders, and neurodegenerative diseases. Trends Neurosci. 2023:46:488–502. 10.1016/j.tins.2023.03.007. PubMed DOI PMC

Altindis  E  et al.  Viral insulin-like peptides activate human insulin and IGF-1 receptor signaling: a paradigm shift for host-microbe interactions. Proc Natl Acad Sci U S A. 2018:115:2461–2466. 10.1073/pnas.1721117115. PubMed DOI PMC

Annunziata  M, Granata  R, Ghigo  E. The IGF system. Acta Diabetol. 2011:48:1–9. 10.1007/s00592-010-0227-z. PubMed DOI

Bach  LA  et al.  Binding of mutants of human insulin-like growth factor II to insulin-like growth factor binding proteins 1-6. J Biol Chem. 1993:268:9246–9254. 10.1016/S0021-9258(18)98342-0. PubMed DOI

Bajaj  M  et al.  Coypu insulin. Primary structure, conformation and biological properties of a hystricomorph rodent insulin. Biochem J. 1986:238:345–351. 10.1042/bj2380345. PubMed DOI PMC

Bathgate  RAD  et al.  Relaxin family peptides and their receptors. Physiol Rev. 2013:93:405–480. 10.1152/physrev.00001.2012. PubMed DOI

Baxter  RC, Bayne  ML, Cascieri  MA. Structural determinants for binary and ternary complex formation between insulin-like growth factor-I (IGF-I) and IGF binding protein-3. J Biol Chem. 1992:267:60–65. 10.1016/S0021-9258(18)48458-X. PubMed DOI

Belfiore  A, Frasca  F, Pandini  G, Sciacca  L, Vigneri  R. Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr Rev. 2009:30:586–623. 10.1210/er.2008-0047. PubMed DOI

Bentley  GA  et al.  Role of B13 Glu in insulin assembly. The hexamer structure of recombinant mutant (B13 Glu–>Gln) insulin. J Mol Biol. 1992:228:1163–1176. 10.1016/0022-2836(92)90323-C. PubMed DOI

Blundell  TL  et al.  Three-dimensional atomic structure of insulin and its relationship to activity. Diabetes. 1972:21:492–505. 10.2337/diab.21.2.S492. PubMed DOI

Blundell  TL, Wood  SP. Is the evolution of insulin Darwinian or due to selectively neutral mutation?  Nature. 1975:257:197–203. 10.1038/257197a0. PubMed DOI

Blyth  AJ, Kirk  NS, Forbes  BE. Understanding IGF-II action through insights into receptor binding and activation. Cells. 2020:9:2276. 10.3390/cells9102276. PubMed DOI PMC

Braun  EJ, Sweazea  KL. Glucose regulation in birds. Comp Biochem Physiol B Biochem Mol Biol. 2008:151:1–9. 10.1016/j.cbpb.2008.05.007. PubMed DOI

Brown  J  et al.  Structure and functional analysis of the IGF-II/IGF2R interaction. EMBO J. 2008:27:265–276. 10.1038/sj.emboj.7601938. PubMed DOI PMC

Brown  J, Jones  EY, Forbes  BE. Interactions of IGF-II with the IGF2R/cation-independent mannose-6-phosphate receptor mechanism and biological outcomes. Vitam Horm. 2009:80:699–719. 10.1016/S0083-6729(08)00625-0. PubMed DOI

Carrick  FE  et al.  Interaction of insulin-like growth factor (IGF)-I and -II with IGF binding protein-2: mapping the binding surfaces by nuclear magnetic resonance. J Mol Endocrinol. 2005:34:685–698. 10.1677/jme.1.01756. PubMed DOI

Chan  SJ, Cao  QP, Steiner  DF. Evolution of the insulin superfamily: cloning of a hybrid insulin/insulin-like growth factor cDNA from amphioxus. Proc Natl Acad Sci U S A. 1990:87:9319–9323. 10.1073/pnas.87.23.9319. PubMed DOI PMC

Chen  C, Jack  J, Garofalo  RS. The PubMed DOI

Chrudinová  M  et al.  A versatile insulin analog with high potency for both insulin and insulin-like growth factor 1 receptors: structural implications for receptor binding. J Biol Chem. 2018:293:16818–16829. 10.1074/jbc.RA118.004852. PubMed DOI PMC

Chrudinová  M  et al.  Characterization of viral insulins reveals white adipose tissue-specific effects in mice. Mol Metab. 2021:44:101121. 10.1016/j.molmet.2020.101121. PubMed DOI PMC

Chrudinová  M  et al.  A viral insulin-like peptide inhibits IGF-1 receptor phosphorylation and regulates IGF1R gene expression. Mol Metab. 2024:80:101863. 10.1016/j.molmet.2023.101863. PubMed DOI PMC

Chuard  A  et al. Viral insulin/IGF-like peptides inhibit IGF-1 receptor signaling to enhance viral replication. PubMed DOI PMC

Conlon  JM. Evolution of the insulin molecule: insights into structure-activity and phylogenetic relationships. Peptides. 2001:22:1183–1193. 10.1016/S0196-9781(01)00423-5. PubMed DOI

Crawford  NG  et al.  More than 1000 ultraconserved elements provide evidence that turtles are the sister group of archosaurs. Biol Lett. 2012:8:783–786. 10.1098/rsbl.2012.0331. PubMed DOI PMC

Cutfield  JF  et al.  Structure and biological activity of hagfish insulin. J Mol Biol. 1979:132:85–100. 10.1016/0022-2836(79)90497-2. PubMed DOI

Darriba  D  et al.  ModelTest-NG: a new and scalable tool for the selection of DNA and protein evolutionary models. Mol Biol Evol. 2020:37:291–294. 10.1093/molbev/msz189. PubMed DOI PMC

De Meyts  P. Insulin/receptor binding: the last piece of the puzzle? What recent progress on the structure of the insulin/receptor complex tells us (or not) about negative cooperativity and activation. Bioessays. 2015:37:389–397. 10.1002/bies.201400190. PubMed DOI

Denley  A, Cosgrove  LJ, Booker  GW, Wallace  JC, Forbes  BE. Molecular interactions of the IGF system. Cytokine Growth Factor Rev. 2005:16:421–439. 10.1016/j.cytogfr.2005.04.004. PubMed DOI

Dimitriadis  G, Mitrou  P, Lambadiari  V, Maratou  E, Raptis  SA. Insulin effects in muscle and adipose tissue. Diabetes Res Clin Pract. 2011:93:S52–S59. 10.1016/S0168-8227(11)70014-6. PubMed DOI

Duguay  SJ, Chan  SJ, Mommsen  TP, Steiner  DF. Divergence of insulin-like growth factors I and II in the elasmobranch, Squalus acanthias. FEBS Lett. 1995:371:69–72. 10.1016/0014-5793(95)00879-E. PubMed DOI

Duret  L, Guex  N, Peitsch  MC, Bairoch  A. New insulin-like proteins with atypical disulfide bond pattern characterized in PubMed DOI

Fernandez  R, Tabarini  D, Azpiazu  N, Frasch  M, Schlessinger  J. The PubMed DOI PMC

Forbes  BE. The three-dimensional structure of insulin and its receptor. Vitam Horm. 2023:123:151–185. 10.1016/bs.vh.2022.12.001. PubMed DOI

Forbes  BE, McCarthy  P, Norton  RS. Insulin-like growth factor binding proteins: a structural perspective. Front Endocrinol. 2012:3:38. 10.3389/fendo.2012.00038. PubMed DOI PMC

Frasca  F  et al.  Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Mol Cell Biol. 1999:19:3278–3288. 10.1128/MCB.19.5.3278. PubMed DOI PMC

Fu  Z, Gilbert  ER, Liu  D. Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes. Curr Diabetes Rev. 2013:9:25–53. 10.2174/157339913804143225. PubMed DOI PMC

Gauguin  L  et al.  Alanine scanning of a putative receptor binding surface of insulin-like growth factor-I. J Biol Chem. 2008:283:20821–20829. 10.1074/jbc.M802620200. PubMed DOI PMC

Girdhar  K  et al.  Viruses and metabolism: the effects of viral infections and viral insulins on host metabolism. Annu Rev Virol. 2021:8:373–391. 10.1146/annurev-virology-091919-102416. PubMed DOI PMC

Gutmann  T  et al.  Cryo-EM structure of the complete and ligand-saturated insulin receptor ectodomain. J Cell Biol. 2020:219:e201907210. 10.1083/jcb.201907210. PubMed DOI PMC

Headey  SJ  et al.  Binding site for the C-domain of insulin-like growth factor (IGF) binding protein-6 on IGF-II; implications for inhibition of IGF actions. FEBS Lett. 2004:568:19–22. 10.1016/j.febslet.2004.04.091. PubMed DOI

Hedges  SB, Poling  LL. A molecular phylogeny of reptiles. Science. 1999:283:998–1001. 10.1126/science.283.5404.998. PubMed DOI

Hernández-Sánchez  C, Mansilla  A, de Pablo  F, Zardoya  R. Evolution of the insulin receptor family and receptor isoform expression in vertebrates. Mol Biol Evol. 2008:25:1043–1053. 10.1093/molbev/msn036. PubMed DOI

Horuk  R  et al.  A monomeric insulin from the porcupine ( PubMed DOI

Huang  Q, Kahn  CR, Altindis  E. Viral hormones: expanding dimensions in endocrinology. Endocrinology. 2019:160:2165–2179. 10.1210/en.2019-00271. PubMed DOI PMC

Irwin  DM. Evolution of the insulin gene: changes in gene number, sequence, and processing. Front Endocrinol. 2021:12:649255. 10.3389/fendo.2021.649255. PubMed DOI PMC

Jin Chan  S, Steiner  DF. Insulin through the ages: phylogeny of a growth promoting and metabolic regulatory hormone. Am Zool. 2000:40:213–222. 10.1093/icb/40.2.213. DOI

Johnson  M  et al.  NCBI BLAST: a better web interface. Nucleic Acids Res. 2008:36:W5–W9. 10.1093/nar/gkn201. PubMed DOI PMC

Katoh  K, Standley  DM. MAFFT multiple sequence alignment software version 7: improvements in performance and usability. Mol Biol Evol. 2013:30:772–780. 10.1093/molbev/mst010. PubMed DOI PMC

Kemmler  W, Peterson  JD, Steiner  DF. Studies on the conversion of proinsulin to insulin. I. Conversion in vitro with trypsin and carboxypeptidase B. J Biol Chem. 1971:246:6786–6791. 10.1016/S0021-9258(19)45914-0. PubMed DOI

Kimura  KD, Tissenbaum  HA, Liu  Y, Ruvkun  G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in PubMed DOI

King  GL, Kahn  CR. Non-parallel evolution of metabolic and growth-promoting functions of insulin. Nature. 1981:292:644–646. 10.1038/292644a0. PubMed DOI

Kozlov  AM, Darriba  D, Flouri  T, Morel  B, Stamatakis  A. RAxML-NG: a fast, scalable and user-friendly tool for maximum likelihood phylogenetic inference. Bioinformatics. 2019:35:4453–4455. 10.1093/bioinformatics/btz305. PubMed DOI PMC

Kremer  LPM, Korb  J, Bornberg-Bauer  E. Reconstructed evolution of insulin receptors in insects reveals duplications in early insects and cockroaches. J Exp Zoolog B Mol Dev Evol. 2018:330:305–311. 10.1002/jez.b.22809. PubMed DOI

Kristensen  C  et al.  Alanine scanning mutagenesis of insulin. J Biol Chem. 1997:272:12978–12983. 10.1074/jbc.272.20.12978. PubMed DOI

Křížková  K  et al.  Insulin-insulin-like growth factors hybrids as molecular probes of hormone:receptor binding specificity. Biochemistry. 2016:55:2903–2913. 10.1021/acs.biochem.6b00140. PubMed DOI

Lemoine  F  et al.  Renewing Felsenstein's phylogenetic bootstrap in the era of big data. Nature. 2018:556:452–456. 10.1038/s41586-018-0043-0. PubMed DOI PMC

Li  C. Neuropeptides. WormBook. 2008:1–36. 10.1895/wormbook.1.142.1. PubMed DOI PMC

Li  J  et al.  Synergistic activation of the insulin receptor via two distinct sites. Nat Struct Mol Biol. 2022:29:357–368. 10.1038/s41594-022-00750-6. PubMed DOI PMC

Li  J, Choi  E, Yu  H, Bai  X-C. Structural basis of the activation of type 1 insulin-like growth factor receptor. Nat Commun. 2019:10:4567. 10.1038/s41467-019-12564-0. PubMed DOI PMC

Lüthi  C, Roth  BV, Humbel  RE. Mutants of human insulin-like growth factor II (IGF II). Expression and characterization of truncated IGF II and of two naturally occurring variants. Eur J Biochem. 1992:205:483–490. 10.1111/j.1432-1033.1992.tb16804.x. PubMed DOI

Macháčková  K  et al.  Mutations at hypothetical binding site 2 in insulin and insulin-like growth factors 1 and 2 result in receptor- and hormone-specific responses. J Biol Chem. 2019:294:17371–17382. 10.1074/jbc.RA119.010072. PubMed DOI PMC

McRory  JE, Sherwood  NM. Ancient divergence of insulin and insulin-like growth factor. DNA Cell Biol. 1997:16:939–949. 10.1089/dna.1997.16.939. PubMed DOI

Menting  JG  et al.  How insulin engages its primary binding site on the insulin receptor. Nature. 2013:493:241–245. 10.1038/nature11781. PubMed DOI PMC

Menting  JG  et al.  Protective hinge in insulin opens to enable its receptor engagement. Proc Natl Acad Sci U S A. 2014:111:E3395–E3404. 10.1073/pnas.1412897111. PubMed DOI PMC

Meyer  A, Zardoya  R. Recent advances in the (molecular) phylogeny of vertebrates. Annu Rev Ecol Evol Syst. 2003:34:311–338. 10.1146/annurev.ecolsys.34.011802.132351. DOI

Mizoguchi  A, Okamoto  N. Insulin-like and IGF-like peptides in the silkmoth PubMed DOI PMC

Moller  DE, Yokota  A, Caro  JF, Flier  JS. Tissue-specific expression of two alternatively spliced insulin receptor mRNAs in man. Mol Endocrinol Baltim Md. 1989:3:1263–1269. 10.1210/mend-3-8-1263. PubMed DOI

Moreau  F  et al.  Interaction of a viral insulin-like peptide with the IGF-1 receptor produces a natural antagonist. Nat Commun. 2022:13:6700. 10.1038/s41467-022-34391-6. PubMed DOI PMC

Muggeo  M  et al.  The insulin receptor in vertebrates is functionally more conserved during evolution than insulin itself. Endocrinology. 1979:104:1393–1402. 10.1210/endo-104-5-1393. PubMed DOI

Mynarcik  DC, Williams  PF, Schaffer  L, Yu  GQ, Whittaker  J. Analog binding properties of insulin receptor mutants. Identification of amino acids interacting with the COOH terminus of the B-chain of the insulin molecule. J Biol Chem. 1997a:272:2077–2081. 10.1074/jbc.272.4.2077. PubMed DOI

Mynarcik  DC, Williams  PF, Schaffer  L, Yu  GQ, Whittaker  J. Identification of common ligand binding determinants of the insulin and insulin-like growth factor 1 receptors. Insights into mechanisms of ligand binding. J Biol Chem. 1997b:272:18650–18655. 10.1074/jbc.272.30.18650. PubMed DOI

Nagamatsu  S, Chan  SJ, Falkmer  S, Steiner  DF. Evolution of the insulin gene superfamily. Sequence of a preproinsulin-like growth factor cDNA from the Atlantic hagfish. J Biol Chem. 1991:266:2397–2402. 10.1016/S0021-9258(18)52257-2. PubMed DOI

Nakae  J, Morioka  H, Ohtsuka  E, Fujieda  K. Replacements of leucine 87 in human insulin receptor alter affinity for insulin. J Biol Chem. 1995:270:22017–22022. 10.1074/jbc.270.37.22017. PubMed DOI

Nässel  DR, Kubrak  OI, Liu  Y, Luo  J, Lushchak  OV. Factors that regulate insulin producing cells and their output in PubMed DOI PMC

Nicol  DS, Smith  LF. Amino-acid sequence of human insulin. Nature. 1960:187:483–485. 10.1038/187483a0. PubMed DOI

Nielsen  J  et al.  Structural investigations of full-length insulin receptor dynamics and signalling. J Mol Biol. 2022:434:167458. 10.1016/j.jmb.2022.167458. PubMed DOI

Okamoto  N  et al.  An ecdysteroid-inducible insulin-like growth factor-like peptide regulates adult development of the silkmoth PubMed DOI

Okamoto  N  et al.  A fat body-derived IGF-like peptide regulates postfeeding growth in PubMed DOI PMC

Pashmforoush  M, Chan  SJ, Steiner  DF. Structure and expression of the insulin-like peptide receptor from amphioxus. Mol Endocrinol Baltim Md. 1996:10:857–866. 10.1210/mend.10.7.8813726. PubMed DOI

Patton  SJ, Luke  GN, Holland  PW. Complex history of a chromosomal paralogy region: insights from amphioxus aromatic amino acid hydroxylase genes and insulin-related genes. Mol Biol Evol. 1998:15:1373–1380. 10.1093/oxfordjournals.molbev.a025865. PubMed DOI

Rao  SS  et al.  Cumulative phylogenetic, sequence and structural analysis of insulin superfamily proteins provide unique structure-function insights. Mol Inform. 2024:43:e202300160. 10.1002/minf.202300160. PubMed DOI

Rentería  ME, Gandhi  NS, Vinuesa  P, Helmerhorst  E, Mancera  RL. A comparative structural bioinformatics analysis of the insulin receptor family ectodomain based on phylogenetic information. PLoS One. 2008:3:e3667. 10.1371/journal.pone.0003667. PubMed DOI PMC

Robinson  DR, Wu  Y-M, Lin  S-F. The protein tyrosine kinase family of the human genome. Oncogene. 2000:19:5548–5557. 10.1038/sj.onc.1203957. PubMed DOI

Rouard  M  et al.  Congenital insulin resistance associated with a conformational alteration in a conserved beta-sheet in the insulin receptor L1 domain. J Biol Chem. 1999:274:18487–18491. 10.1074/jbc.274.26.18487. PubMed DOI

Safavi-Hemami  H  et al.  Specialized insulin is used for chemical warfare by fish-hunting cone snails. Proc Natl Acad Sci U S A. 2015:112:1743–1748. 10.1073/pnas.1423857112. PubMed DOI PMC

Sajid  W  et al.  Structural basis of the aberrant receptor binding properties of hagfish and lamprey insulins. Biochemistry. 2009:48:11283–11295. 10.1021/bi901269j. PubMed DOI PMC

Satoh  T. Bird evolution by insulin resistance. Trends Endocrinol Metab. 2021:32:803–813. 10.1016/j.tem.2021.07.007. PubMed DOI

Scapin  G  et al.  Structure of the insulin receptor-insulin complex by single-particle cryo-EM analysis. Nature. 2018:556:122–125. 10.1038/nature26153. PubMed DOI PMC

Schumacher  R, Mosthaf  L, Schlessinger  J, Brandenburg  D, Ullrich  A. Insulin and insulin-like growth factor-1 binding specificity is determined by distinct regions of their cognate receptors. J Biol Chem. 1991:266:19288–19295. 10.1016/S0021-9258(18)54996-6. PubMed DOI

Seino  S, Bell  GI. Alternative splicing of human insulin receptor messenger RNA. Biochem Biophys Res Commun. 1989:159:312–316. 10.1016/0006-291X(89)92439-X. PubMed DOI

Semaniuk  U  et al. DOI

Simon  J, Freychet  P, Rosselin  G. Chicken insulin: radioimmunological characterization and enhanced activity in rat fat cells and liver plasma membranes. Endocrinology. 1974:95:1439–1449. 10.1210/endo-95-5-1439. PubMed DOI

Smýkal  V  et al.  Complex evolution of insect insulin receptors and homologous decoy receptors, and functional significance of their multiplicity. Mol Biol Evol. 2020:37:1775–1789. 10.1093/molbev/msaa048. PubMed DOI PMC

Steiner  DF, Chan  SJ, Welsh  JM, Kwok  SC. Structure and evolution of the insulin gene. Annu Rev Genet. 1985:19:463–484. 10.1146/annurev.ge.19.120185.002335. PubMed DOI

Sweazea  KL. Revisiting glucose regulation in birds—a negative model of diabetes complications. Comp Biochem Physiol B Biochem Mol Biol. 2022:262:110778. 10.1016/j.cbpb.2022.110778. PubMed DOI

Thorsøe  KS  et al.  Kinetic evidence for the sequential association of insulin binding sites 1 and 2 to the insulin receptor and the influence of receptor isoform. Biochemistry. 2010:49:6234–6246. 10.1021/bi1000118. PubMed DOI

Torres  AM  et al.  Solution structure of human insulin-like growth factor II. Relationship to receptor and binding protein interactions. J Mol Biol. 1995:248:385–401. 10.1016/S0022-2836(95)80058-1. PubMed DOI

Uchikawa  E, Choi  E, Shang  G, Yu  H, Bai  X-C. Activation mechanism of the insulin receptor revealed by cryo-EM structure of the fully liganded receptor-ligand complex. eLife. 2019:8:e48630. 10.7554/eLife.48630. PubMed DOI PMC

Vajdos  FF  et al.  Crystal structure of human insulin-like growth factor-1: detergent binding inhibits binding protein interactions. Biochemistry. 2001:40:11022–11029. 10.1021/bi0109111. PubMed DOI

Wagih  O. Ggseqlogo: a versatile R package for drawing sequence logos. Bioinforma Oxf Engl. 2017:33:3645–3647. 10.1093/bioinformatics/btx469. PubMed DOI

Whittaker  J  et al.  Alanine scanning mutagenesis of a type 1 insulin-like growth factor receptor ligand binding site. J Biol Chem. 2001:276:43980–43986. 10.1074/jbc.M102863200. PubMed DOI

Whittaker  J, Sørensen  H, Gadsbøll  VL, Hinrichsen  J. Comparison of the functional insulin binding epitopes of the A and B isoforms of the insulin receptor. J Biol Chem. 2002:277:47380–47384. 10.1074/jbc.M208371200. PubMed DOI

Whittaker  L, Hao  C, Fu  W, Whittaker  J. High-affinity insulin binding: insulin interacts with two receptor ligand binding sites. Biochemistry. 2008:47:12900–12909. 10.1021/bi801693h. PubMed DOI PMC

Williams  C  et al.  An exon splice enhancer primes IGF2:IGF2R binding site structure and function evolution. Science. 2012:338:1209–1213. 10.1126/science.1228633. PubMed DOI PMC

Williams  PF, Mynarcik  DC, Yu  GQ, Whittaker  J. Mapping of an NH2-terminal ligand binding site of the insulin receptor by alanine scanning mutagenesis. J Biol Chem. 1995:270:3012–3016. 10.1074/jbc.270.7.3012. PubMed DOI

Xu  Y  et al.  How ligand binds to the type 1 insulin-like growth factor receptor. Nat Commun. 2018:9:821. 10.1038/s41467-018-03219-7. PubMed DOI PMC

Xu  Y  et al.  How IGF-II binds to the human type 1 insulin-like growth factor receptor. Structure. 2020:28:786–798.e6. 10.1016/j.str.2020.05.002. PubMed DOI PMC

Yamagishi  G, Yoshida  A, Kobayashi  A, Park  MK. Molecular characterization of insulin from squamate reptiles reveals sequence diversity and possible adaptive evolution. Gen Comp Endocrinol. 2016:225:197–211. 10.1016/j.ygcen.2015.08.021. PubMed DOI

Zesławski  W  et al.  The interaction of insulin-like growth factor-I with the N-terminal domain of IGFBP-5. EMBO J. 2001:20:3638–3644. 10.1093/emboj/20.14.3638. PubMed DOI PMC

Zhang  F, Altindis  E, Kahn  CR, DiMarchi  RD, Gelfanov  V. A viral insulin-like peptide is a natural competitive antagonist of the human IGF-1 receptor. Mol Metab. 2021:53:101316. 10.1016/j.molmet.2021.101316. PubMed DOI PMC

Zhu  R, Chin-Sang  ID. PubMed DOI

Zoete  V, Meuwly  M, Karplus  M. Study of the insulin dimerization: binding free energy calculations and per-residue free energy decomposition. Proteins. 2005:61:79–93. 10.1002/prot.20528. PubMed DOI