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Crystal structure of the alpha1beta1 integrin I domain in complex with an antibody Fab fragment.

Karpusas M, Ferrant J, Weinreb PH, Carmillo A, Taylor FR, Garber EA
J Mol Biol 327 1031-41 (2003)
Cited: 26 times
EuropePMC logo PMID: 12662928

Abstract

The alpha1beta1 (VLA-1) integrin is a cell-surface receptor for collagen and laminin and has been implicated in biological pathways involved in several pathological processes. These processes may be inhibited by the monoclonal antibody AQC2, which binds with high affinity to human alpha1beta1 integrin. To understand the structural basis of the inhibition we determined the crystal structure of the complex of a chimeric rat/human I domain of the alpha1beta1 integrin and the Fab fragment of humanized AQC2 antibody. The structure of the complex shows that the antibody blocks the collagen binding site of the I domain. An aspartate residue, from the CDR3 loop of the antibody heavy chain, coordinates the MIDAS metal ion in a manner similar to that of a glutamate residue from collagen. Substitution of the aspartate residue by alanine or arginine results in significant reduction of antibody binding affinity. Interestingly, although the mode of metal ion coordination resembles that of the open conformation, the I domain maintains an overall closed conformation previously observed only for unliganded I domains.

Reviews - 1mhp mentioned but not cited (1)

  1. Computer-aided antibody design. Kuroda D, Shirai H, Jacobson MP, Nakamura H. Protein Eng Des Sel 25 507-521 (2012)

Articles - 1mhp mentioned but not cited (10)

  1. Affinity enhancement of an in vivo matured therapeutic antibody using structure-based computational design. Clark LA, Boriack-Sjodin PA, Eldredge J, Fitch C, Friedman B, Hanf KJ, Jarpe M, Liparoto SF, Li Y, Lugovskoy A, Miller S, Rushe M, Sherman W, Simon K, Van Vlijmen H. Protein Sci 15 949-960 (2006)
  2. Prediction of antigenic epitopes on protein surfaces by consensus scoring. Liang S, Zheng D, Zhang C, Zacharias M. BMC Bioinformatics 10 302 (2009)
  3. Mining for the antibody-antigen interacting associations that predict the B cell epitopes. Zhao L, Li J. BMC Struct Biol 10 Suppl 1 S6 (2010)
  4. RosettaAntibodyDesign (RAbD): A general framework for computational antibody design. Adolf-Bryfogle J, Kalyuzhniy O, Kubitz M, Weitzner BD, Hu X, Adachi Y, Schief WR, Dunbrack RL. PLoS Comput Biol 14 e1006112 (2018)
  5. Stable coordination of the inhibitory Ca2+ ion at the metal ion-dependent adhesion site in integrin CD11b/CD18 by an antibody-derived ligand aspartate: implications for integrin regulation and structure-based drug design. Mahalingam B, Ajroud K, Alonso JL, Anand S, Adair BD, Horenstein AL, Malavasi F, Xiong JP, Arnaout MA. J Immunol 187 6393-6401 (2011)
  6. Structural basis of activation-dependent binding of ligand-mimetic antibody AL-57 to integrin LFA-1. Zhang H, Zhang H, Liu JH, Yang W, Springer T, Shimaoka M, Wang JH. Proc Natl Acad Sci U S A 106 18345-18350 (2009)
  7. Augmented Binary Substitution: Single-pass CDR germ-lining and stabilization of therapeutic antibodies. Townsend S, Fennell BJ, Apgar JR, Lambert M, McDonnell B, Grant J, Wade J, Franklin E, Foy N, Ní Shúilleabháin D, Fields C, Darmanin-Sheehan A, King A, Paulsen JE, Hickling TP, Tchistiakova L, Cunningham O, Finlay WJ. Proc Natl Acad Sci U S A 112 15354-15359 (2015)
  8. Dynamic structural changes are observed upon collagen and metal ion binding to the integrin α1 I domain. Weinreb PH, Li S, Gao SX, Liu T, Pepinsky RB, Caravella JA, Lee JH, Woods VL. J Biol Chem 287 32897-32912 (2012)
  9. A meta-learning approach for B-cell conformational epitope prediction. Hu YJ, Lin SC, Lin YL, Lin KH, You SN. BMC Bioinformatics 15 378 (2014)
  10. Guidelines To Predict Binding Poses of Antibody-Integrin Complexes. Chaves B, Sartori GR, Vasconcelos DCA, Savino W, Caffarena ER, Cotta-de-Almeida V, da Silva JHM. ACS Omega 5 16379-16385 (2020)


Reviews citing this publication (4)

  1. Integrin structure, allostery, and bidirectional signaling. Arnaout MA, Mahalingam B, Xiong JP. Annu Rev Cell Dev Biol 21 381-410 (2005)
  2. Integrin signaling in malignant melanoma. Kuphal S, Bauer R, Bosserhoff AK. Cancer Metastasis Rev 24 195-222 (2005)
  3. Integrin modulators: a patent review. Kapp TG, Rechenmacher F, Sobahi TR, Kessler H. Expert Opin Ther Pat 23 1273-1295 (2013)
  4. Integrin signaling in cancer: bidirectional mechanisms and therapeutic opportunities. Li S, Sampson C, Liu C, Piao HL, Liu HX. Cell Commun Signal 21 266 (2023)

Articles citing this publication (11)

  1. Conversion between three conformational states of integrin I domains with a C-terminal pull spring studied with molecular dynamics. Jin M, Andricioaei I, Springer TA. Structure 12 2137-2147 (2004)
  2. AL-57, a ligand-mimetic antibody to integrin LFA-1, reveals chemokine-induced affinity up-regulation in lymphocytes. Shimaoka M, Kim M, Cohen EH, Yang W, Astrof N, Peer D, Salas A, Ferrand A, Springer TA. Proc Natl Acad Sci U S A 103 13991-13996 (2006)
  3. In vitro sortagging of an antibody fab fragment: overcoming unproductive reactions of sortase with water and lysine side chains. Möhlmann S, Mahlert C, Greven S, Scholz P, Harrenga A. Chembiochem 12 1774-1780 (2011)
  4. A monoclonal antibody to alpha1beta1 blocks antigen-induced airway responses in sheep. Abraham WM, Ahmed A, Serebriakov I, Carmillo AN, Ferrant J, de Fougerolles AR, Garber EA, Gotwals PJ, Koteliansky VE, Taylor F, Lobb RR. Am J Respir Crit Care Med 169 97-104 (2004)
  5. Efalizumab binding to the LFA-1 alphaL I domain blocks ICAM-1 binding via steric hindrance. Li S, Wang H, Peng B, Zhang M, Zhang D, Hou S, Guo Y, Ding J. Proc Natl Acad Sci U S A 106 4349-4354 (2009)
  6. Crystal structure of EMS16 in complex with the integrin alpha2-I domain. Horii K, Okuda D, Morita T, Mizuno H. J Mol Biol 341 519-527 (2004)
  7. Integrin α1 has a long helix, extending from the transmembrane region to the cytoplasmic tail in detergent micelles. Lai C, Liu X, Tian C, Wu F. PLoS One 8 e62954 (2013)
  8. The testosterone binding mechanism of an antibody derived from a naïve human scFv library. Niemi MH, Takkinen K, Amundsen LK, Söderlund H, Rouvinen J, Höyhtyä M. J Mol Recognit 24 209-219 (2011)
  9. An antibody loop replacement design feasibility study and a loop-swapped dimer structure. Clark LA, Boriack-Sjodin PA, Day E, Eldredge J, Fitch C, Jarpe M, Miller S, Li Y, Simon K, van Vlijmen HW. Protein Eng Des Sel 22 93-101 (2009)
  10. Influence of canonical structure determining residues on antibody affinity and stability. Clark LA, Demarest SJ, Eldredge J, Jarpe MB, Li Y, Simon K, van Vlijmen HW. J Struct Biol 185 223-227 (2014)
  11. Magnesium Activates Microsecond Dynamics to Regulate Integrin-Collagen Recognition. Nunes AM, Minetti CASA, Remeta DP, Baum J. Structure 26 1080-1090.e5 (2018)


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