PDBsum entry 1aap

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Proteinase inhibitor (trypsin) PDB id
Protein chains
56 a.a. *
Waters ×105
* Residue conservation analysis
PDB id:
Name: Proteinase inhibitor (trypsin)
Title: X-ray crystal structure of the protease inhibitor domain of alzheimer's amyloid beta-protein precursor
Structure: Alzheimer's disease amyloid a4 protein. Chain: a, b. Fragment: inhibitor domain. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
1.50Å     R-factor:   0.177    
Authors: T.R.Hynes,M.Randal,L.A.Kennedy,C.Eigenbrot,A.A.Kossiakoff
Key ref:
T.R.Hynes et al. (1990). X-ray crystal structure of the protease inhibitor domain of Alzheimer's amyloid beta-protein precursor. Biochemistry, 29, 10018-10022. PubMed id: 2125487 DOI: 10.1021/bi00495a002
14-Sep-90     Release date:   15-Oct-91    
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Protein chains
Pfam   ArchSchema ?
P05067  (A4_HUMAN) -  Amyloid beta A4 protein
770 a.a.
56 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     nervous system development   1 term 
  Biochemical function     serine-type endopeptidase inhibitor activity     1 term  


DOI no: 10.1021/bi00495a002 Biochemistry 29:10018-10022 (1990)
PubMed id: 2125487  
X-ray crystal structure of the protease inhibitor domain of Alzheimer's amyloid beta-protein precursor.
T.R.Hynes, M.Randal, L.A.Kennedy, C.Eigenbrot, A.A.Kossiakoff.
Alzheimer's amyloid beta-protein precursor contains a Kunitz protease inhibitor domain (APPI) potentially involved in proteolytic events leading to cerebral amyloid deposition. To facilitate the identification of the physiological target of the inhibitor, the crystal structure of APPI has been determined and refined to 1.5-A resolution. Sequences in the inhibitor-protease interface of the correct protease target will reflect the molecular details of the APPI structure. While the overall tertiary fold of APPI is very similar to that of the Kunitz inhibitor BPTI, a significant rearrangement occurs in the backbone conformation of one of the two protease binding loops. A number of Kunitz inhibitors have similar loop sequences, indicating the structural alteration is conserved and potentially an important determinant of inhibitor specificity. In a separate region of the protease binding loops, APPI side chains Met-17 and Phe-34 create an exposed hydrophobic surface in place of Arg-17 and Val-34 in BPTI. The restriction this change places on protease target sequences is seen when the structure of APPI is superimposed on BPTI complexed to serine proteases, where the hydrophobic surface of APPI faces a complementary group of nonpolar side chains on kallikrein A versus polar side chains on trypsin.

Literature references that cite this PDB file's key reference

  PubMed id Reference
20180638 J.E.Swedberg, Veer, and J.M.Harris (2010).
Natural and engineered kallikrein inhibitors: an emerging pharmacopoeia.
  Biol Chem, 391, 357-374.  
18702528 A.J.Beel, C.K.Mobley, H.J.Kim, F.Tian, A.Hadziselimovic, B.Jap, J.H.Prestegard, and C.R.Sanders (2008).
Structural studies of the transmembrane C-terminal domain of the amyloid precursor protein (APP): does APP function as a cholesterol sensor?
  Biochemistry, 47, 9428-9446.  
18182389 D.Kaden, L.M.Munter, M.Joshi, C.Treiber, C.Weise, T.Bethge, P.Voigt, M.Schaefer, M.Beyermann, B.Reif, and G.Multhaup (2008).
Homophilic interactions of the amyloid precursor protein (APP) ectodomain are regulated by the loop region and affect beta-secretase cleavage of APP.
  J Biol Chem, 283, 7271-7279.  
18286181 S.Macedo-Ribeiro, C.Almeida, B.M.Calisto, T.Friedrich, R.Mentele, J.Stürzebecher, P.Fuentes-Prior, and P.J.Pereira (2008).
Isolation, cloning and structural characterisation of boophilin, a multifunctional Kunitz-type proteinase inhibitor from the cattle tick.
  PLoS ONE, 3, e1624.
PDB code: 2ody
17428603 M.Gralle, and S.T.Ferreira (2007).
Structure and functions of the human amyloid precursor protein: the whole is more than the sum of its parts.
  Prog Neurobiol, 82, 11-32.  
16830095 A.Chakrabarty, J.A.MacLean, A.L.Hughes, R.M.Roberts, and J.A.Green (2006).
Rapid evolution of the trophoblast kunitz domain proteins (TKDPs)-a multigene family in ruminant ungulates.
  J Mol Evol, 63, 274-282.  
16805778 C.L.Masters, R.Cappai, K.J.Barnham, and V.L.Villemagne (2006).
Molecular mechanisms for Alzheimer's disease: implications for neuroimaging and therapeutics.
  J Neurochem, 97, 1700-1725.  
16085935 D.Navaneetham, L.Jin, P.Pandey, J.E.Strickler, R.E.Babine, S.S.Abdel-Meguid, and P.N.Walsh (2005).
Structural and mutational analyses of the molecular interactions between the catalytic domain of factor XIa and the Kunitz protease inhibitor domain of protease nexin 2.
  J Biol Chem, 280, 36165-36175.
PDB code: 1zjd
16102414 S.Herrero, E.Combes, M.M.Van Oers, J.M.Vlak, Maagd, and J.Beekwilder (2005).
Identification and recombinant expression of a novel chymotrypsin from Spodoptera exigua.
  Insect Biochem Mol Biol, 35, 1073-1082.  
15090552 A.E.Schmidt, T.Ogawa, D.Gailani, and S.P.Bajaj (2004).
Structural role of Gly(193) in serine proteases: investigations of a G555E (GLY193 in chymotrypsin) mutant of blood coagulation factor XI.
  J Biol Chem, 279, 29485-29492.  
15333934 C.Keil, R.Huber, W.Bode, and M.E.Than (2004).
Cloning, expression, crystallization and initial crystallographic analysis of the C-terminal domain of the amyloid precursor protein APP.
  Acta Crystallogr D Biol Crystallogr, 60, 1614-1617.  
12796495 M.G.Botelho, M.Gralle, C.L.Oliveira, I.Torriani, and S.T.Ferreira (2003).
Folding and stability of the extracellular domain of the human amyloid precursor protein.
  J Biol Chem, 278, 34259-34267.  
12496118 M.Gralle, M.M.Botelho, Oliveira, I.Torriani, and S.T.Ferreira (2002).
Solution studies and structural model of the extracellular domain of the human amyloid precursor protein.
  Biophys J, 83, 3513-3524.  
10684650 I.Favre, G.W.Moss, D.P.Goldenberg, J.Otlewski, and E.Moczydlowski (2000).
Structure-activity relationships for the interaction of bovine pancreatic trypsin inhibitor with an intracellular site on a large conductance Ca(2+)-activated K(+) channel.
  Biochemistry, 39, 2001-2012.  
10769134 K.O.Badellino, and P.N.Walsh (2000).
Protease nexin II interactions with coagulation factor XIa are contained within the Kunitz protease inhibitor domain of protease nexin II and the factor XIa catalytic domain.
  Biochemistry, 39, 4769-4777.  
10081964 B.Gilquin, A.Lecoq, F.Desné, M.Guenneugues, S.Zinn-Justin, and A.Ménez (1999).
Conformational and functional variability supported by the BPTI fold: solution structure of the Ca2+ channel blocker calcicludine.
  Proteins, 34, 520-532.
PDB code: 1bf0
9478949 R.D.Moir, T.Lynch, A.I.Bush, S.Whyte, A.Henry, S.Portbury, G.Multhaup, D.H.Small, R.E.Tanzi, K.Beyreuther, and C.L.Masters (1998).
Relative increase in Alzheimer's disease of soluble forms of cerebral Abeta amyloid protein precursor containing the Kunitz protease inhibitory domain.
  J Biol Chem, 273, 5013-5019.  
  9614193 S.H.Wong, T.Zhang, Y.Xu, V.N.Subramaniam, G.Griffiths, and W.Hong (1998).
Endobrevin, a novel synaptobrevin/VAMP-like protein preferentially associated with the early endosome.
  Mol Biol Cell, 9, 1549-1563.  
9417091 S.H.Wong, Y.Xu, T.Zhang, and W.Hong (1998).
Syntaxin 7, a novel syntaxin member associated with the early endosomal compartment.
  J Biol Chem, 273, 375-380.  
  9300481 A.J.Scheidig, T.R.Hynes, L.A.Pelletier, J.A.Wells, and A.A.Kossiakoff (1997).
Crystal structures of bovine chymotrypsin and trypsin complexed to the inhibitor domain of Alzheimer's amyloid beta-protein precursor (APPI) and basic pancreatic trypsin inhibitor (BPTI): engineering of inhibitors with altered specificities.
  Protein Sci, 6, 1806-1824.
PDB codes: 1ca0 1cbw 1taw
9179777 C.Capasso, M.Rizzi, E.Menegatti, P.Ascenzi, and M.Bolognesi (1997).
Crystal structure of the bovine alpha-chymotrypsin:Kunitz inhibitor complex. An example of multiple protein:protein recognition sites.
  J Mol Recognit, 10, 26-35.
PDB code: 1mtn
9094090 J.Y.Duffy, M.L.Stallings-Mann, W.E.Trout, and R.M.Roberts (1997).
Expression of a plasmin/trypsin Kunitz inhibitor by pig trophoblast.
  Mol Reprod Dev, 46, 443-449.  
9265624 M.D.Sorensen, S.Bjorn, K.Norris, O.Olsen, L.Petersen, T.L.James, and J.J.Led (1997).
Solution structure and backbone dynamics of the human alpha3-chain type VI collagen C-terminal Kunitz domain,.
  Biochemistry, 36, 10439-10450.
PDB code: 1kun
9238642 A.C.Ley, W.Markland, and R.C.Ladner (1996).
Obtaining a family of high-affinity, high-specificity protein inhibitors of plasmin and plasma kallikrein.
  Mol Divers, 2, 119-124.  
8681942 E.Kohfeldt, W.Göhring, U.Mayer, M.Zweckstetter, T.A.Holak, M.L.Chu, and R.Timpl (1996).
Conversion of the Kunitz-type module of collagen VI into a highly active trypsin inhibitor by site-directed mutagenesis.
  Eur J Biochem, 238, 333-340.  
8631347 L.C.Petersen, S.E.Bjørn, O.H.Olsen, O.Nordfang, F.Norris, and K.Norris (1996).
Inhibitory properties of separate recombinant Kunitz-type-protease-inhibitor domains from tissue-factor-pathway inhibitor.
  Eur J Biochem, 235, 310-316.  
8805527 M.Zweckstetter, M.Czisch, U.Mayer, M.L.Chu, W.Zinth, R.Timpl, and T.A.Holak (1996).
Structure and multiple conformations of the kunitz-type domain from human type VI collagen alpha3(VI) chain in solution.
  Structure, 4, 195-209.  
8672509 W.Markland, A.C.Ley, S.W.Lee, and R.C.Ladner (1996).
Iterative optimization of high-affinity proteases inhibitors using phage display. 1. Plasmin.
  Biochemistry, 35, 8045-8057.  
7592708 M.S.Dennis, A.Herzka, and R.A.Lazarus (1995).
Potent and selective Kunitz domain inhibitors of plasma kallikrein designed by phage display.
  J Biol Chem, 270, 25411-25417.  
  7538849 M.S.Lim-Wilby, K.Hallenga, Maeyer, I.Lasters, G.P.Vlasuk, and T.K.Brunck (1995).
NMR structure determination of tick anticoagulant peptide (TAP).
  Protein Sci, 4, 178-186.
PDB code: 1tcp
8590005 P.D.Kwong, N.Q.McDonald, P.B.Sigler, and W.A.Hendrickson (1995).
Structure of beta 2-bungarotoxin: potassium channel binding by Kunitz modules and targeted phospholipase action.
  Structure, 3, 1109-1119.
PDB code: 1bun
7546567 R.C.Ladner (1995).
Constrained peptides as binding entities.
  Trends Biotechnol, 13, 426-430.  
8302860 H.Schweitz, C.Heurteaux, P.Bois, D.Moinier, G.Romey, and M.Lazdunski (1994).
Calcicludine, a venom peptide of the Kunitz-type protease inhibitor family, is a potent blocker of high-threshold Ca2+ channels with a high affinity for L-type channels in cerebellar granule neurons.
  Proc Natl Acad Sci U S A, 91, 878-882.  
8306991 K.Sorimachi, and D.J.Craik (1994).
Structure determination of extracellular fragments of amyloid proteins involved in Alzheimer's disease and Dutch-type hereditary cerebral haemorrhage with amyloidosis.
  Eur J Biochem, 219, 237-251.  
7525281 U.Mayer, E.Pöschl, R.Nischt, U.Specks, T.C.Pan, M.L.Chu, and R.Timpl (1994).
Recombinant expression and properties of the Kunitz-type protease-inhibitor module from human type VI collagen alpha 3(VI) chain.
  Eur J Biochem, 225, 573-580.  
  7686069 K.S.Kim, F.Tao, J.Fuchs, A.T.Danishefsky, D.Housset, A.Wlodawer, and C.Woodward (1993).
Crevice-forming mutants of bovine pancreatic trypsin inhibitor: stability changes and new hydrophobic surface.
  Protein Sci, 2, 588-596.  
8291086 T.E.Creighton, and J.Kemmink (1993).
NOGGIN is unlikely to be homologous to the Kunitz protease-inhibitor family.
  Trends Biochem Sci, 18, 424-426.  
8462542 W.Antuch, K.D.Berndt, M.A.Chávez, J.Delfín, and K.Wüthrich (1993).
The NMR solution structure of a Kunitz-type proteinase inhibitor from the sea anemone Stichodactyla helianthus.
  Eur J Biochem, 212, 675-684.
PDB code: 1shp
1470680 M.Billeter (1992).
Comparison of protein structures determined by NMR in solution and by X-ray diffraction in single crystals.
  Q Rev Biophys, 25, 325-377.  
1528078 M.D.Walkinshaw (1992).
Protein targets for structure-based drug design.
  Med Res Rev, 12, 317-372.  
1541261 W.Bode, and R.Huber (1992).
Natural protein proteinase inhibitors and their interaction with proteinases.
  Eur J Biochem, 204, 433-451.  
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.