PDBsum entry 1aut

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Hydrolase/hydrolase inhibitor PDB id
Protein chains
240 a.a. *
98 a.a. *
Waters ×438
* Residue conservation analysis
PDB id:
Name: Hydrolase/hydrolase inhibitor
Title: Human activated protein c
Structure: Activated protein c. Chain: c. Synonym: autoprothrombin iia. Other_details: gla-domain removed by chymotrypsin. Activated protein c. Chain: l. Synonym: autoprothrombin iia. Other_details: gla-domain removed by chymotrypsin
Source: Homo sapiens. Human. Organism_taxid: 9606. Organ: plasma. Tissue: plasma. Tissue: plasma
Biol. unit: Not given
2.80Å     R-factor:   0.184    
Authors: T.Mather,V.Oganessyan,P.Hof,W.Bode,R.Huber,S.Foundling,C.Esm
Key ref: T.Mather et al. (1996). The 2.8 A crystal structure of Gla-domainless activated protein C. EMBO J, 15, 6822-6831. PubMed id: 9003757
08-Jun-96     Release date:   20-Aug-97    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P04070  (PROC_HUMAN) -  Vitamin K-dependent protein C
461 a.a.
240 a.a.
Protein chain
Pfam   ArchSchema ?
P04070  (PROC_HUMAN) -  Vitamin K-dependent protein C
461 a.a.
98 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: Chains C, L: E.C.  - Protein C (activated).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Degradation of blood coagulation factors Va and VIIIa.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     proteolysis   1 term 
  Biochemical function     catalytic activity     3 terms  


EMBO J 15:6822-6831 (1996)
PubMed id: 9003757  
The 2.8 A crystal structure of Gla-domainless activated protein C.
T.Mather, V.Oganessyan, P.Hof, R.Huber, S.Foundling, C.Esmon, W.Bode.
The structure of the Gla-domainless form of the human anticoagulant enzyme activated protein C has been solved at 2.8 A resolution. The light chain is composed of two domains: an epidermal growth factor (EGF)-like domain modified by a large insert containing an additional disulfide, followed by a typical EGF-like domain. The arrangement of the long axis of these domains describes an angle of approximately 80 degrees. Disulfide linked to the light chain is the catalytic domain, which is generally trypsin-like but contains a large insertion loop at the edge of the active site, a third helical segment, a prominent cationic patch analogous to the anion binding exosite I of thrombin and a trypsin-like Ca[II] binding site. The arrangement of loops around the active site partially restricts access to the cleft. The S2 and S4 subsites are much more polar than in factor Xa and thrombin, and the S2 site is unrestricted. While quite open and exposed, the active site contains a prominent groove, the surface of which is very polar with evidence for binding sites on the primed side, in addition to those typical of the trypsin class found on the non-primed side.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21353711 B.V.Zlokovic, and J.H.Griffin (2011).
Cytoprotective protein C pathways and implications for stroke and neurological disorders.
  Trends Neurosci, 34, 198-209.  
21406063 C.S.Craik, M.J.Page, and E.L.Madison (2011).
Proteases as therapeutics.
  Biochem J, 435, 1.  
  21457218 T.J.Cramer, and A.J.Gale (2011).
Function of the activated protein C (APC) autolysis loop in activated FVIII inactivation.
  Br J Haematol, 153, 644-654.  
20423310 A.R.Rezaie (2010).
Regulation of the protein C anticoagulant and antiinflammatory pathways.
  Curr Med Chem, 17, 2059-2069.  
19995397 P.P.Sarangi, H.W.Lee, and M.Kim (2010).
Activated protein C action in inflammation.
  Br J Haematol, 148, 817-833.  
19498029 E.Di Cera (2009).
Know your APC.
  Blood, 113, 5699-5700.  
19244161 G.F.Elphick, P.P.Sarangi, Y.M.Hyun, J.A.Hollenbaugh, A.Ayala, W.L.Biffl, H.L.Chung, A.R.Rezaie, J.L.McGrath, D.J.Topham, J.S.Reichner, and M.Kim (2009).
Recombinant human activated protein C inhibits integrin-mediated neutrophil migration.
  Blood, 113, 4078-4085.  
  19956450 J.Wang, and J.Li (2009).
Activated protein C: a potential cardioprotective factor against ischemic injury during ischemia/reperfusion.
  Am J Transl Res, 1, 381-392.  
19790056 K.Ede, K.K.Hwang, C.C.Wu, M.Wu, Y.H.Yang, W.S.Lin, D.Chien, P.C.Chen, B.P.Tsao, D.K.McCurdy, and P.P.Chen (2009).
Plasmin immunization preferentially induces potentially prothrombotic IgG anticardiolipin antibodies in MRL/MpJ mice.
  Arthritis Rheum, 60, 3108-3117.  
19774207 L.Altaweel, D.Sweeney, X.Cui, A.Barochia, C.Natanson, and P.Qeichacker (2009).
Growing insights into the potential benefits and risks of activated protein C administration in sepsis: a review of preclinical and clinical studies.
  Biologics, 3, 391-406.  
19244160 L.O.Mosnier, A.Zampolli, E.J.Kerschen, R.A.Schuepbach, Y.Banerjee, J.A.Fernández, X.V.Yang, M.Riewald, H.Weiler, Z.M.Ruggeri, and J.H.Griffin (2009).
Hyperantithrombotic, noncytoprotective Glu149Ala-activated protein C mutant.
  Blood, 113, 5970-5978.  
19133979 R.J.Preston, C.Morse, S.L.Murden, S.K.Brady, J.S.O'Donnell, and A.D.Mumford (2009).
The protein C omega-loop substitution Asn2Ile is associated with reduced protein C anticoagulant activity.
  Br J Haematol, 144, 946-953.  
19640005 S.H.Qureshi, L.Yang, C.Manithody, A.V.Iakhiaev, and A.R.Rezaie (2009).
Mutagenesis studies toward understanding allostery in thrombin.
  Biochemistry, 48, 8261-8270.  
18058827 R.E.Saunders, and S.J.Perkins (2008).
CoagMDB: a database analysis of missense mutations within four conserved domains in five vitamin K-dependent coagulation serine proteases using a text-mining tool.
  Hum Mutat, 29, 333-344.  
18329782 S.H.Qureshi, C.Manithody, J.S.Bae, L.Yang, and A.R.Rezaie (2008).
Autolysis loop restricts the specificity of activated protein C: analysis by FRET and functional assays.
  Biophys Chem, 134, 239-245.  
18493021 V.Chandrasekaran, C.J.Lee, R.E.Duke, L.Perera, and L.G.Pedersen (2008).
Computational study of the putative active form of protein Z (PZa): sequence design and structural modeling.
  Protein Sci, 17, 1354-1361.  
17456189 C.J.Lee, V.Chandrasekaran, R.E.Duke, L.Perera, and L.G.Pedersen (2007).
A proposed structural model of human protein Z.
  J Thromb Haemost, 5, 1558-1561.  
17152060 E.Rovida, G.Merati, P.D'Ursi, S.Zanardelli, F.Marino, G.Fontana, G.Castaman, and E.M.Faioni (2007).
Identification and computationally-based structural interpretation of naturally occurring variants of human protein C.
  Hum Mutat, 28, 345-355.  
17519239 F.Varfaj, H.Wakabayashi, and P.J.Fay (2007).
Residues surrounding Arg336 and Arg562 contribute to the disparate rates of proteolysis of factor VIIIa catalyzed by activated protein C.
  J Biol Chem, 282, 20264-20272.  
17635713 J.H.Griffin, J.A.Fernández, A.J.Gale, and L.O.Mosnier (2007).
Activated protein C.
  J Thromb Haemost, 5, 73-80.  
17872949 L.O.Mosnier, X.V.Yang, and J.H.Griffin (2007).
Activated protein C mutant with minimal anticoagulant activity, normal cytoprotective activity, and preservation of thrombin activable fibrinolysis inhibitor-dependent cytoprotective functions.
  J Biol Chem, 282, 33022-33033.  
17580306 L.Yang, J.S.Bae, C.Manithody, and A.R.Rezaie (2007).
Identification of a specific exosite on activated protein C for interaction with protease-activated receptor 1.
  J Biol Chem, 282, 25493-25500.  
17387172 M.Ndonwi, G.J.Broze, S.Agah, A.E.Schmidt, and S.P.Bajaj (2007).
Substitution of the Gla domain in factor X with that of protein C impairs its interaction with factor VIIa/tissue factor: lack of comparable effect by similar substitution in factor IX.
  J Biol Chem, 282, 15632-15644.  
17430555 P.D'Ursi, F.Marino, A.Caprera, L.Milanesi, E.M.Faioni, and E.Rovida (2007).
ProCMD: a database and 3D web resource for protein C mutants.
  BMC Bioinformatics, 8, S11.  
17635714 P.E.Bock, P.Panizzi, and I.M.Verhamme (2007).
Exosites in the substrate specificity of blood coagulation reactions.
  J Thromb Haemost, 5, 81-94.  
17456194 T.Hayashi, J.Nishioka, N.Nakagawa, H.Kamada, E.C.Gabazza, T.Kobayashi, A.Hattori, and K.Suzuki (2007).
Protein C inhibitor directly and potently inhibits activated hepatocyte growth factor activator.
  J Thromb Haemost, 5, 1477-1485.  
17469158 W.S.Lin, P.C.Chen, C.D.Yang, E.Cho, B.H.Hahn, J.Grossman, K.K.Hwang, and P.P.Chen (2007).
Some antiphospholipid antibodies recognize conformational epitopes shared by beta2-glycoprotein I and the homologous catalytic domains of several serine proteases.
  Arthritis Rheum, 56, 1638-1647.  
16418283 L.Yang, C.Manithody, and A.R.Rezaie (2006).
Activation of protein C by the thrombin-thrombomodulin complex: cooperative roles of Arg-35 of thrombin and Arg-67 of protein C.
  Proc Natl Acad Sci U S A, 103, 879-884.  
16757484 S.P.Bajaj, A.E.Schmidt, S.Agah, M.S.Bajaj, and K.Padmanabhan (2006).
High resolution structures of p-aminobenzamidine- and benzamidine-VIIa/soluble tissue factor: unpredicted conformation of the 192-193 peptide bond and mapping of Ca2+, Mg2+, Na+, and Zn2+ sites in factor VIIa.
  J Biol Chem, 281, 24873-24888.
PDB codes: 2a2q 2aer 2fir
  17114499 Y.H.Yang, K.K.Hwang, J.FitzGerald, J.M.Grossman, M.Taylor, B.H.Hahn, and P.P.Chen (2006).
Antibodies against the activated coagulation factor X (FXa) in the antiphospholipid syndrome that interfere with the FXa inactivation by antithrombin.
  J Immunol, 177, 8219-8225.  
15632123 A.G.Olivero, C.Eigenbrot, R.Goldsmith, K.Robarge, D.R.Artis, J.Flygare, T.Rawson, D.P.Sutherlin, S.Kadkhodayan, M.Beresini, L.O.Elliott, G.G.DeGuzman, D.W.Banner, M.Ultsch, U.Marzec, S.R.Hanson, C.Refino, S.Bunting, and D.Kirchhofer (2005).
A selective, slow binding inhibitor of factor VIIa binds to a nonstandard active site conformation and attenuates thrombus formation in vivo.
  J Biol Chem, 280, 9160-9169.
PDB code: 1ygc
16320350 C.S.Lu, A.A.Horizon, K.K.Hwang, J.FitzGerald, W.S.Lin, B.H.Hahn, D.J.Wallace, A.L.Metzger, M.H.Weisman, and P.P.Chen (2005).
Identification of polyclonal and monoclonal antibodies against tissue plasminogen activator in the antiphospholipid syndrome.
  Arthritis Rheum, 52, 4018-4027.  
15705565 G.Lu, S.Chhum, and S.Krishnaswamy (2005).
The affinity of protein C for the thrombin.thrombomodulin complex is determined in a primary way by active site-dependent interactions.
  J Biol Chem, 280, 15471-15478.  
  16113785 L.Yang, C.Manithody, and A.R.Rezaie (2005).
The functional significance of the autolysis loop in protein C and activated protein C.
  Thromb Haemost, 94, 60-68.  
16162508 M.T.Murakami, and R.K.Arni (2005).
Thrombomodulin-independent activation of protein C and specificity of hemostatically active snake venom serine proteinases: crystal structures of native and inhibited Agkistrodon contortrix contortrix protein C activator.
  J Biol Chem, 280, 39309-39315.
PDB codes: 2aip 2aiq
15892855 W.Bode (2005).
The structure of thrombin, a chameleon-like proteinase.
  J Thromb Haemost, 3, 2379-2388.  
14747992 A.J.Gale, and J.H.Griffin (2004).
Characterization of a thrombomodulin binding site on protein C and its comparison to an activated protein C binding site for factor Va.
  Proteins, 54, 433-441.  
15206937 G.A.Nicolaes, K.W.Sørensen, U.Friedrich, G.Tans, J.Rosing, L.Autin, B.Dahlbäck, and B.O.Villoutreix (2004).
Altered inactivation pathway of factor Va by activated protein C in the presence of heparin.
  Eur J Biochem, 271, 2724-2736.  
15219196 H.C.Whinna, E.B.Lesesky, D.M.Monroe, K.A.High, P.J.Larson, and F.C.Church (2004).
Role of the gamma-carboxyglutamic acid domain of activated factor X in the presence of calcium during inhibition by antithrombin-heparin.
  J Thromb Haemost, 2, 1127-1134.  
14739327 L.Chen, C.Manithody, L.Yang, and A.R.Rezaie (2004).
Zymogenic and enzymatic properties of the 70-80 loop mutants of factor X/Xa.
  Protein Sci, 13, 431-442.  
15254039 L.Yang, S.Prasad, E.Di Cera, and A.R.Rezaie (2004).
The conformation of the activation peptide of protein C is influenced by Ca2+ and Na+ binding.
  J Biol Chem, 279, 38519-38524.  
15331602 S.Yegneswaran, R.M.Mesters, J.A.Fernández, and J.H.Griffin (2004).
Prothrombin residues 473-487 contribute to factor Va binding in the prothrombinase complex.
  J Biol Chem, 279, 49019-49025.  
14523228 A.R.Rezaie, and L.Yang (2003).
Thrombomodulin allosterically modulates the activity of the anticoagulant thrombin.
  Proc Natl Acad Sci U S A, 100, 12051-12056.  
12871288 B.Dahlbäck, and B.O.Villoutreix (2003).
Molecular recognition in the protein C anticoagulant pathway.
  J Thromb Haemost, 1, 1525-1534.  
12671072 D.T.Berg, B.Gerlitz, J.Shang, T.Smith, P.Santa, M.A.Richardson, K.D.Kurz, B.W.Grinnell, K.Mace, and B.E.Jones (2003).
Engineering the proteolytic specificity of activated protein C improves its pharmacological properties.
  Proc Natl Acad Sci U S A, 100, 4423-4428.  
12794830 K.K.Hwang, C.D.Yang, W.Yan, J.M.Grossman, B.H.Hahn, and P.P.Chen (2003).
A thrombin-cross-reactive anticardiolipin antibody binds to and inhibits the anticoagulant function of activated protein C.
  Arthritis Rheum, 48, 1622-1630.  
12444082 K.Sichler, E.Kopetzki, R.Huber, W.Bode, K.P.Hopfner, and H.Brandstetter (2003).
Physiological fIXa activation involves a cooperative conformational rearrangement of the 99-loop.
  J Biol Chem, 278, 4121-4126.  
12871399 P.C.Liaw, G.Ferrell, and C.T.Esmon (2003).
A monoclonal antibody against activated protein C allows rapid detection of activated protein C in plasma and reveals a calcium ion dependent epitope involved in factor Va inactivation.
  J Thromb Haemost, 1, 662-670.  
12029084 A.E.Schmidt, K.Padmanabhan, M.C.Underwood, W.Bode, T.Mather, and S.P.Bajaj (2002).
Thermodynamic linkage between the S1 site, the Na+ site, and the Ca2+ site in the protease domain of human activated protein C (APC). Sodium ion in the APC crystal structure is coordinated to four carbonyl groups from two separate loops.
  J Biol Chem, 277, 28987-28995.
PDB code: 3f6u
12063259 A.J.Gale, A.Tsavaler, and J.H.Griffin (2002).
Molecular characterization of an extended binding site for coagulation factor Va in the positive exosite of activated protein C.
  J Biol Chem, 277, 28836-28840.  
12124990 B.N.Terp, D.N.Cooper, I.T.Christensen, F.S.Jørgensen, P.Bross, N.Gregersen, and M.Krawczak (2002).
Assessing the relative importance of the biophysical properties of amino acid substitutions associated with human genetic disease.
  Hum Mutat, 20, 98.  
11723140 D.Zhong, M.S.Bajaj, A.E.Schmidt, and S.P.Bajaj (2002).
The N-terminal epidermal growth factor-like domain in factor IX and factor X represents an important recognition motif for binding to tissue factor.
  J Biol Chem, 277, 3622-3631.  
12364340 K.Soejima, M.Yuguchi, J.Mizuguchi, K.Tomokiyo, T.Nakashima, T.Nakagaki, and S.Iwanaga (2002).
The 99 and 170 loop-modified factor VIIa mutants show enhanced catalytic activity without tissue factor.
  J Biol Chem, 277, 49027-49035.  
12034704 V.Oganesyan, N.Oganesyan, S.Terzyan, D.Qu, Z.Dauter, N.L.Esmon, and C.T.Esmon (2002).
The crystal structure of the endothelial protein C receptor and a bound phospholipid.
  J Biol Chem, 277, 24851-24854.
PDB codes: 1l8j 1lqv
10775260 C.Gaboriaud, V.Rossi, I.Bally, G.J.Arlaud, and J.C.Fontecilla-Camps (2000).
Crystal structure of the catalytic domain of human complement c1s: a serine protease with a handle.
  EMBO J, 19, 1755-1765.
PDB code: 1elv
11123896 K.Strandberg, M.Kjellberg, E.M.Erb, U.Persson, D.F.Mosher, B.O.Villoutreix, and J.Stenflo (2000).
Activated protein C-protein C inhibitor complex formation: characterization of a neoepitope provides evidence for extensive insertion of the reactive center loop.
  Biochemistry, 39, 15713-15720.  
11106601 L.Perera, C.Foley, T.A.Darden, D.Stafford, T.Mather, C.T.Esmon, and L.G.Pedersen (2000).
Modeling zymogen protein C.
  Biophys J, 79, 2925-2943.  
10715104 L.Shen, B.Dahlbäck, and B.O.Villoutreix (2000).
Tracking structural features leading to resistance of activated protein C to alpha 1-antitrypsin.
  Biochemistry, 39, 2853-2860.  
10681521 P.C.Liaw, P.F.Neuenschwander, M.D.Smirnov, and C.T.Esmon (2000).
Mechanisms by which soluble endothelial cell protein C receptor modulates protein C and activated protein C function.
  J Biol Chem, 275, 5447-5452.  
10430872 A.C.Pike, A.M.Brzozowski, S.M.Roberts, O.H.Olsen, and E.Persson (1999).
Structure of human factor VIIa and its implications for the triggering of blood coagulation.
  Proc Natl Acad Sci U S A, 96, 8925-8930.
PDB code: 1qfk
10373456 A.Mathur, and S.P.Bajaj (1999).
Protease and EGF1 domains of factor IXa play distinct roles in binding to factor VIIIa. Importance of helix 330 (helix 162 in chymotrypsin) of protease domain of factor IXa in its interaction with factor VIIIa.
  J Biol Chem, 274, 18477-18486.  
10102985 H.Czapinska, and J.Otlewski (1999).
Structural and energetic determinants of the S1-site specificity in serine proteases.
  Eur J Biochem, 260, 571-595.  
10223294 K.E.Knobe, A.Berntsdotter, L.Shen, J.Morser, B.Dahlbäck, and B.O.Villoutreix (1999).
Probing the activation of protein C by the thrombin-thrombomodulin complex using structural analysis, site-directed mutagenesis, and computer modeling.
  Proteins, 35, 218-234.  
9988741 X.He, and A.R.Rezaie (1999).
Identification and characterization of the sodium-binding site of activated protein C.
  J Biol Chem, 274, 4970-4976.  
9642241 A.R.Rezaie (1998).
Calcium enhances heparin catalysis of the antithrombin-factor Xa reaction by a template mechanism. Evidence that calcium alleviates Gla domain antagonism of heparin binding to factor Xa.
  J Biol Chem, 273, 16824-16827.  
  9655335 B.O.Villoutreix, and B.Dahlbäck (1998).
Structural investigation of the A domains of human blood coagulation factor V by molecular modeling.
  Protein Sci, 7, 1317-1325.  
9525966 G.Kemball-Cook, D.J.Johnson, O.Takamiya, D.W.Banner, J.H.McVey, and E.G.Tuddenham (1998).
Coagulation factor VII Gln100 --> Arg. Amino acid substitution at the epidermal growth factor 2-protease domain interface results in severely reduced tissue factor binding and procoagulant function.
  J Biol Chem, 273, 8516-8521.  
9618463 K.Kamata, H.Kawamoto, T.Honma, T.Iwama, and S.H.Kim (1998).
Structural basis for chemical inhibition of human blood coagulation factor Xa.
  Proc Natl Acad Sci U S A, 95, 6630-6635.
PDB codes: 1xka 1xkb
9707558 K.P.Hopfner, E.Kopetzki, G.B.Kresse, W.Bode, R.Huber, and R.A.Engh (1998).
New enzyme lineages by subdomain shuffling.
  Proc Natl Acad Sci U S A, 95, 9813-9818.
PDB code: 1fxy
9664841 T.M.Hackeng, P.E.Dawson, S.B.Kent, and J.H.Griffin (1998).
Chemical synthesis of human protein S thrombin-sensitive module and first epidermal growth factor module.
  Biopolymers, 46, 53-63.  
9362477 K.P.Hopfner, H.Brandstetter, A.Karcher, E.Kopetzki, R.Huber, R.A.Engh, and W.Bode (1997).
Converting blood coagulation factor IXa into factor Xa: dramatic increase in amidolytic activity identifies important active site determinants.
  EMBO J, 16, 6626-6635.  
9305622 M.Renatus, R.A.Engh, M.T.Stubbs, R.Huber, S.Fischer, U.Kohnert, and W.Bode (1997).
Lysine 156 promotes the anomalous proenzyme activity of tPA: X-ray crystal structure of single-chain human tPA.
  EMBO J, 16, 4797-4805.
PDB code: 1bda
9218519 S.Kurosawa, D.J.Stearns-Kurosawa, N.Hidari, and C.T.Esmon (1997).
Identification of functional endothelial protein C receptor in human plasma.
  J Clin Invest, 100, 411-418.  
9312108 S.Yegneswaran, G.M.Wood, C.T.Esmon, and A.E.Johnson (1997).
Protein S alters the active site location of activated protein C above the membrane surface. A fluorescence resonance energy transfer study of topography.
  J Biol Chem, 272, 25013-25021.  
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 codes are shown on the right.