PDBsum entry 1a4y

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protein Protein-protein interface(s) links
Complex (inhibitor/nuclease) PDB id
Protein chains
460 a.a. *
123 a.a. *
Waters ×133
* Residue conservation analysis
PDB id:
Name: Complex (inhibitor/nuclease)
Title: Ribonuclease inhibitor-angiogenin complex
Structure: Ribonuclease inhibitor. Chain: a, d. Engineered: yes. Angiogenin. Chain: b, e. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Organ: placenta. Expressed in: escherichia coli str. K12 substr. W3110. Expression_system_taxid: 316407.
Biol. unit: Tetramer (from PQS)
2.00Å     R-factor:   0.193     R-free:   0.286
Authors: A.C.Papageorgiou,K.R.Acharya
Key ref:
A.C.Papageorgiou et al. (1997). Molecular recognition of human angiogenin by placental ribonuclease inhibitor--an X-ray crystallographic study at 2.0 A resolution. EMBO J, 16, 5162-5177. PubMed id: 9311977 DOI: 10.1093/emboj/16.17.5162
08-Feb-98     Release date:   14-Oct-98    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P13489  (RINI_HUMAN) -  Ribonuclease inhibitor
461 a.a.
460 a.a.
Protein chains
Pfam   ArchSchema ?
P03950  (ANGI_HUMAN) -  Angiogenin
147 a.a.
123 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   12 terms 
  Biological process     nucleic acid phosphodiester bond hydrolysis   30 terms 
  Biochemical function     protein binding     15 terms  


DOI no: 10.1093/emboj/16.17.5162 EMBO J 16:5162-5177 (1997)
PubMed id: 9311977  
Molecular recognition of human angiogenin by placental ribonuclease inhibitor--an X-ray crystallographic study at 2.0 A resolution.
A.C.Papageorgiou, R.Shapiro, K.R.Acharya.
Human placental RNase inhibitor (hRI), a leucine-rich repeat protein, binds the blood vessel-inducing protein human angiogenin (Ang) with extraordinary affinity (Ki <1 fM). Here we report a 2.0 A resolution crystal structure for the hRI-Ang complex that, together with extensive mutagenesis data from earlier studies, reveals the molecular features of this tight interaction. The hRI-Ang binding interface is large and encompasses 26 residues from hRI and 24 from Ang, recruited from multiple domains of both proteins. However, a substantial fraction of the energetically important contacts involve only a single region of each: the C-terminal segment 434-460 of hRI and the ribonucleolytic active centre of Ang, most notably the catalytic residue Lys40. Although the overall docking of Ang resembles that observed for RNase A in the crystal structure of its complex with the porcine RNase inhibitor, the vast majority of the interactions in the two complexes are distinctive, indicating that the broad specificity of the inhibitor for pancreatic RNase superfamily proteins is based largely on its capacity to recognize features unique to each of them. The implications of these findings for the development of small, hRI-based inhibitors of Ang for therapeutic use are discussed.
  Selected figure(s)  
Figure 4.
Figure 4 Stereo views of hRI (A) and Ang (B) (C^ atoms plus side chains of contact residues), and hRI (thick lines, upper case letters) plus Ang (thin lines, lower case letters) together (contact residues only) (C) in the hRI -Ang complex.
Figure 5.
Figure 5 (A -E) Detailed interactions at the hRI -Ang interface. hRI residues have filled bonds; Ang residues have empty bonds. Drawn with the program MOLSCRIPT (Kraulis, 1991).
  The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: EMBO J (1997, 16, 5162-5177) copyright 1997.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21155806 G.J.Wright, and P.Washbourne (2011).
Neurexins, neuroligins and LRRTMs: synaptic adhesion getting fishy.
  J Neurochem, 117, 765-778.  
21125316 J.Chen, X.Ou-Yang, J.Gao, J.Zhu, X.He, and J.Rong (2011).
Knockdown of ribonuclease inhibitor expression with siRNA in non-invasive bladder cancer cell line BIU-87 promotes growth and metastasis potentials.
  Mol Cell Biochem, 349, 83-95.  
20544968 D.J.Diller, C.Humblet, X.Zhang, and L.M.Westerhoff (2010).
Computational alanine scanning with linear scaling semiempirical quantum mechanical methods.
  Proteins, 78, 2329-2337.  
19354288 K.A.Dickson, D.K.Kang, Y.S.Kwon, J.C.Kim, P.A.Leland, B.M.Kim, S.I.Chang, and R.T.Raines (2009).
Ribonuclease inhibitor regulates neovascularization by human angiogenin.
  Biochemistry, 48, 3804-3806.  
19452560 K.L.Hindle, J.Bella, and S.C.Lovell (2009).
Quantitative analysis and prediction of curvature in leucine-rich repeat proteins.
  Proteins, 77, 342-358.  
18446235 M.Proell, S.J.Riedl, J.H.Fritz, A.M.Rojas, and R.Schwarzenbacher (2008).
The Nod-like receptor (NLR) family: a tale of similarities and differences.
  PLoS ONE, 3, e2119.  
18214954 Q.R.Fan, and W.A.Hendrickson (2008).
Comparative structural analysis of the binding domain of follicle stimulating hormone receptor.
  Proteins, 72, 393-401.  
18673284 T.J.Rutkoski, and R.T.Raines (2008).
Evasion of ribonuclease inhibitor as a determinant of ribonuclease cytotoxicity.
  Curr Pharm Biotechnol, 9, 185-189.  
18069884 A.Del Sol, and P.Carbonell (2007).
The Modular Organization of Domain Structures: Insights into Protein-Protein Binding.
  PLoS Comput Biol, 3, e239.  
17925020 A.Shulman-Peleg, M.Shatsky, R.Nussinov, and H.J.Wolfson (2007).
Spatial chemical conservation of hot spot interactions in protein-protein complexes.
  BMC Biol, 5, 43.  
17559675 D.Dell'Orco, P.G.De Benedetti, and F.Fanelli (2007).
In silico screening of mutational effects on enzyme-proteic inhibitor affinity: a docking-based approach.
  BMC Struct Biol, 7, 37.  
17883850 D.S.Osorio, A.Antunes, and M.J.Ramos (2007).
Structural and functional implications of positive selection at the primate angiogenin gene.
  BMC Evol Biol, 7, 167.  
17192264 H.M.Kim, S.C.Oh, K.J.Lim, J.Kasamatsu, J.Y.Heo, B.S.Park, H.Lee, O.J.Yoo, M.Kasahara, and J.O.Lee (2007).
Structural diversity of the hagfish variable lymphocyte receptors.
  J Biol Chem, 282, 6726-6732.
PDB codes: 2o6q 2o6r 2o6s
17471552 J.Ko, and E.Kim (2007).
Leucine-rich repeat proteins of synapses.
  J Neurosci Res, 85, 2824-2832.  
17517123 N.Matsushima, T.Tanaka, P.Enkhbayar, T.Mikami, M.Taga, K.Yamada, and Y.Kuroki (2007).
Comparative sequence analysis of leucine-rich repeats (LRRs) within vertebrate toll-like receptors.
  BMC Genomics, 8, 124.  
17350650 R.J.Johnson, J.G.McCoy, C.A.Bingman, G.N.Phillips, and R.T.Raines (2007).
Inhibition of human pancreatic ribonuclease by the human ribonuclease inhibitor protein.
  J Mol Biol, 368, 434-449.
PDB codes: 1z7x 2q4g
17956129 R.J.Johnson, L.D.Lavis, and R.T.Raines (2007).
Intraspecies regulation of ribonucleolytic activity.
  Biochemistry, 46, 13131-13140.  
16861230 E.Pizzo, P.Buonanno, A.Di Maro, S.Ponticelli, S.De Falco, N.Quarto, M.V.Cubellis, and G.D'Alessio (2006).
Ribonucleases and angiogenins from fish.
  J Biol Chem, 281, 27454-27460.  
16406303 L.Federici, A.Di Matteo, J.Fernandez-Recio, D.Tsernoglou, and F.Cervone (2006).
Polygalacturonase inhibiting proteins: players in plant innate immunity?
  Trends Plant Sci, 11, 65-70.  
16803891 T.Nitto, K.D.Dyer, M.Czapiga, and H.F.Rosenberg (2006).
Evolution and function of leukocyte RNase A ribonucleases of the avian species, Gallus gallus.
  J Biol Chem, 281, 25622-25634.  
15695505 E.E.Büllesbach, and C.Schwabe (2005).
The trap-like relaxin-binding site of the leucine-rich G-protein-coupled receptor 7.
  J Biol Chem, 280, 14051-14056.  
15778086 J.X.Chen, Y.Gao, J.W.Liu, Y.X.Tian, J.Zhao, and X.Y.Cui (2005).
Antitumor effects of human ribonuclease inhibitor gene transfected on B16 melanoma cells.
  Int J Biochem Cell Biol, 37, 1219-1231.  
16164979 K.A.Dickson, M.C.Haigis, and R.T.Raines (2005).
Ribonuclease inhibitor: structure and function.
  Prog Nucleic Acid Res Mol Biol, 80, 349-374.  
16373579 M.N.Alder, I.B.Rogozin, L.M.Iyer, G.V.Glazko, M.D.Cooper, and Z.Pancer (2005).
Diversity and function of adaptive immune receptors in a jawless vertebrate.
  Science, 310, 1970-1973.  
15596504 T.Haliloglu, O.Keskin, B.Ma, and R.Nussinov (2005).
How similar are protein folding and protein binding nuclei? Examination of vibrational motions of energy hot spots and conserved residues.
  Biophys J, 88, 1552-1559.  
15645301 Z.Wang, L.Zhang, J.Lu, and L.Zhang (2005).
Analysis of the interactions of ribonuclease inhibitor with kanamycin.
  J Mol Model, 11, 80-86.  
14681553 K.Kumar, M.Brady, and R.Shapiro (2004).
Selective abolition of pancreatic RNase binding to its inhibitor protein.
  Proc Natl Acad Sci U S A, 101, 53-58.  
14734555 L.B.Clark, P.Viswanathan, G.Quigley, Y.C.Chiang, J.S.McMahon, G.Yao, J.Chen, A.Nelsbach, and C.L.Denis (2004).
Systematic mutagenesis of the leucine-rich repeat (LRR) domain of CCR4 reveals specific sites for binding to CAF1 and a separate critical role for the LRR in CCR4 deadenylase activity.
  J Biol Chem, 279, 13616-13623.  
14747988 P.Enkhbayar, M.Kamiya, M.Osaki, T.Matsumoto, and N.Matsushima (2004).
Structural principles of leucine-rich repeat (LRR) proteins.
  Proteins, 54, 394-403.  
15501918 P.G.Scott, P.A.McEwan, C.M.Dodd, E.M.Bergmann, P.N.Bishop, and J.Bella (2004).
Crystal structure of the dimeric protein core of decorin, the archetypal small leucine-rich repeat proteoglycan.
  Proc Natl Acad Sci U S A, 101, 15633-15638.
PDB codes: 1xcd 1xec 1xku
15211521 S.Lu, J.Symersky, S.Li, M.Carson, L.Chen, E.Meehan, and M.Luo (2004).
Structural genomics of Caenorhabditis elegans: crystal structure of the tropomodulin C-terminal domain.
  Proteins, 56, 384-386.
PDB code: 1pgv
15044951 T.Tanabe, M.Chamaillard, Y.Ogura, L.Zhu, S.Qiu, J.Masumoto, P.Ghosh, A.Moran, M.M.Predergast, G.Tromp, C.J.Williams, N.Inohara, and G.Núñez (2004).
Regulatory regions and critical residues of NOD2 involved in muramyl dipeptide recognition.
  EMBO J, 23, 1587-1597.  
12709057 A.Bracale, F.Castaldi, L.Nitsch, and G.D'Alessio (2003).
A role for the intersubunit disulfides of seminal RNase in the mechanism of its antitumor action.
  Eur J Biochem, 270, 1980-1987.  
14552836 J.K.Bell, G.E.Mullen, C.A.Leifer, A.Mazzoni, D.R.Davies, and D.M.Segal (2003).
Leucine-rich repeats and pathogen recognition in Toll-like receptors.
  Trends Immunol, 24, 528-533.  
12560499 M.C.Haigis, E.L.Kurten, and R.T.Raines (2003).
Ribonuclease inhibitor as an intracellular sentry.
  Nucleic Acids Res, 31, 1024-1032.  
12791136 M.P.Machner, S.Frese, W.D.Schubert, V.Orian-Rousseau, E.Gherardi, J.Wehland, H.H.Niemann, and D.W.Heinz (2003).
Aromatic amino acids at the surface of InlB are essential for host cell invasion by Listeria monocytogenes.
  Mol Microbiol, 48, 1525-1536.  
12834403 N.Baumberger, M.Steiner, U.Ryser, B.Keller, and C.Ringli (2003).
Synergistic interaction of the two paralogous Arabidopsis genes LRX1 and LRX2 in cell wall formation during root hair development.
  Plant J, 35, 71-81.  
12839991 W.A.Barton, B.P.Liu, D.Tzvetkova, P.D.Jeffrey, A.E.Fournier, D.Sah, R.Cate, S.M.Strittmatter, and D.B.Nikolov (2003).
Structure and axon outgrowth inhibitor binding of the Nogo-66 receptor and related proteins.
  EMBO J, 22, 3291-3302.
PDB code: 1p8t
14661268 W.D.Schubert, and D.W.Heinz (2003).
Structural aspects of adhesion to and invasion of host cells by the human pathogen Listeria monocytogenes.
  Chembiochem, 4, 1285-1291.  
12377788 A.Russo, A.Antignani, C.Giancola, and G.D'Alessio (2002).
Engineering the refolding pathway and the quaternary structure of seminal ribonuclease by newly introduced disulfide bridges.
  J Biol Chem, 277, 48643-48649.  
12226088 H.Ceulemans, V.Vulsteke, M.De Maeyer, K.Tatchell, W.Stalmans, and M.Bollen (2002).
Binding of the concave surface of the Sds22 superhelix to the alpha 4/alpha 5/alpha 6-triangle of protein phosphatase-1.
  J Biol Chem, 277, 47331-47337.  
12414704 I.Krieger, A.Kostyukova, A.Yamashita, Y.Nitanai, and Y.Maéda (2002).
Crystal structure of the C-terminal half of tropomodulin and structural basis of actin filament pointed-end capping.
  Biophys J, 83, 2716-2725.
PDB code: 1io0
12105206 M.Santra, C.C.Reed, and R.V.Iozzo (2002).
Decorin binds to a narrow region of the epidermal growth factor (EGF) receptor, partially overlapping but distinct from the EGF-binding epitope.
  J Biol Chem, 277, 35671-35681.  
  18628868 B.Mattei, F.Cervone, and P.Roepstorff (2001).
The Interaction Between Endopolygalacturonase From Fusarium Moniliforme and PGIP from Phaseolus Vulgaris Studied by Surface Plasmon Resonance and Mass Spectrometry.
  Comp Funct Genomics, 2, 359-364.  
11701868 G.De Lorenzo, R.D'Ovidio, and F.Cervone (2001).
The role of polygalacturonase-inhibiting proteins (PGIPs) in defense against pathogenic fungi.
  Annu Rev Phytopathol, 39, 313-335.  
11264578 J.Pous, G.Mallorquí-Fernández, R.Peracaula, S.S.Terzyan, J.Futami, H.Tada, H.Yamada, M.Seno, Llorens, F.X.Gomis-Rüth, and M.Coll (2001).
Three-dimensional structure of human RNase 1 delta N7 at 1.9 A resolution.
  Acta Crystallogr D Biol Crystallogr, 57, 498-505.
PDB code: 1e21
11358688 P.A.Leland, and R.T.Raines (2001).
Cancer chemotherapy--ribonucleases to the rescue.
  Chem Biol, 8, 405-413.  
10938095 J.A.Harton, and J.P.Ting (2000).
Class II transactivator: mastering the art of major histocompatibility complex expression.
  Mol Cell Biol, 20, 6185-6194.  
10973092 J.Ellis, P.Dodds, and T.Pryor (2000).
The generation of plant disease resistance gene specificities.
  Trends Plant Sci, 5, 373-379.  
10922035 M.Marino, L.Braun, P.Cossart, and P.Ghosh (2000).
A framework for interpreting the leucine-rich repeats of the Listeria internalins.
  Proc Natl Acad Sci U S A, 97, 8784-8788.  
10656267 N.Matsushima, T.Ohyanagi, T.Tanaka, and R.H.Kretsinger (2000).
Super-motifs and evolution of tandem leucine-rich repeats within the small proteoglycans--biglycan, decorin, lumican, fibromodulin, PRELP, keratocan, osteoadherin, epiphycan, and osteoglycin.
  Proteins, 38, 210-225.  
11003667 S.B.Hake, K.Masternak, C.Kammerbauer, C.Janzen, W.Reith, and V.Steimle (2000).
CIITA leucine-rich repeats control nuclear localization, in vivo recruitment to the major histocompatibility complex (MHC) class II enhanceosome, and MHC class II gene transactivation.
  Mol Cell Biol, 20, 7716-7725.  
  10048337 B.M.Kim, L.W.Schultz, and R.T.Raines (1999).
Variants of ribonuclease inhibitor that resist oxidation.
  Protein Sci, 8, 430-434.  
10413501 C.Z.Chen, and R.Shapiro (1999).
Superadditive and subadditive effects of "hot spot" mutations within the interfaces of placental ribonuclease inhibitor with angiogenin and ribonuclease A.
  Biochemistry, 38, 9273-9285.  
10228150 F.Leckie, B.Mattei, C.Capodicasa, A.Hemmings, L.Nuss, B.Aracri, G.De Lorenzo, and F.Cervone (1999).
The specificity of polygalacturonase-inhibiting protein (PGIP): a single amino acid substitution in the solvent-exposed beta-strand/beta-turn region of the leucine-rich repeats (LRRs) confers a new recognition capability.
  EMBO J, 18, 2352-2363.  
10635330 M.Marino, L.Braun, P.Cossart, and P.Ghosh (1999).
Structure of the lnlB leucine-rich repeats, a domain that triggers host cell invasion by the bacterial pathogen L. monocytogenes.
  Mol Cell, 4, 1063-1072.
PDB code: 1d0b
10394366 R.C.Hillig, L.Renault, I.R.Vetter, T.Drell, A.Wittinghofer, and J.Becker (1999).
The crystal structure of rna1p: a new fold for a GTPase-activating protein.
  Mol Cell, 3, 781-791.
PDB code: 1yrg
9724716 P.A.Leland, L.W.Schultz, B.M.Kim, and R.T.Raines (1998).
Ribonuclease A variants with potent cytotoxic activity.
  Proc Natl Acad Sci U S A, 95, 10407-10412.  
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