ACK1 is a multidomain non-receptor tyrosine kinase that is an effector of the Cdc42 GTPase. Members of the ACK family have a unique domain ordering and are the only tyrosine kinases known to interact with Cdc42. In contrast with many protein kinases, ACK1 has only a modest increase in activity upon phosphorylation. We have solved the crystal structures of the human ACK1 kinase domain in both the unphosphorylated and phosphorylated states. Comparison of these structures reveals that ACK1 adopts an activated conformation independent of phosphorylation. Furthermore, the unphosphorylated activation loop is structured, and its conformation resembles that seen in activated tyrosine kinases. In addition to the apo structure, complexes are also presented with a non-hydrolyzable nucleotide analog (adenosine 5′-(β,γ-methylenetriphosphate)) and with the natural product debromohymenialdisine, a general inhibitor of many protein kinases. Analysis of these structures reveals a typical kinase fold, a pre-organization into the activated conformation, and an unusual substrate-binding cleft. ACK1 is a multidomain non-receptor tyrosine kinase that is an effector of the Cdc42 GTPase. Members of the ACK family have a unique domain ordering and are the only tyrosine kinases known to interact with Cdc42. In contrast with many protein kinases, ACK1 has only a modest increase in activity upon phosphorylation. We have solved the crystal structures of the human ACK1 kinase domain in both the unphosphorylated and phosphorylated states. Comparison of these structures reveals that ACK1 adopts an activated conformation independent of phosphorylation. Furthermore, the unphosphorylated activation loop is structured, and its conformation resembles that seen in activated tyrosine kinases. In addition to the apo structure, complexes are also presented with a non-hydrolyzable nucleotide analog (adenosine 5′-(β,γ-methylenetriphosphate)) and with the natural product debromohymenialdisine, a general inhibitor of many protein kinases. Analysis of these structures reveals a typical kinase fold, a pre-organization into the activated conformation, and an unusual substrate-binding cleft. ACK1 (activated Cdc42-associated kinase-1) is a member of a small family of non-receptor tyrosine kinases that bind Cdc42 in its GTP-bound form. Members of the ACK family have been identified in many species, including human (TNK1) (1Hoehn G.T. Stokland T. Amin S. Ramirez M. Hawkins A.L. Griffin C.A. Small D. Civin C.I. Oncogene. 1996; 12: 903-913PubMed Google Scholar), cow (ACK2) (2Yang W. Cerione R.A. J. Biol. Chem. 1997; 272: 24819-24824Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar), Drosophila (DAck, DPR2) (3Worby C.A. Simonson-Leff N. Clemens J.C. Huddler Jr., D. Muda M. Dixon J.E. J. Biol. Chem. 2002; 277: 9422-9428Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 4Ito M. Matsui T. Taniguchi T. Chihara K. Gene (Amst.). 1994; 139: 215-218Crossref PubMed Scopus (11) Google Scholar), and Caenorhabditis elegans (ARK1) (5Hopper N.A. Lee J. Sternberg P.W. Mol. Cell. 2000; 6: 65-75Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). ACK1 is a multidomain protein, and all family members contain an SH3 1The abbreviations used are: SH3, Src homology 3; EGFR, epidermal growth factor receptor; ACK1K, ACK1 kinase domain; AMP-PCP, adenosine 5′-(β,γ-methylenetriphosphate); r.m.s.d., root mean square deviation; EGFRK, epidermal growth factor receptor kinase domain; CRIB, cdc42/Rac interactive binding domain. domain and a C-terminal proline-rich region. ACK family members are largely expressed in brain and skeletal tissue (2Yang W. Cerione R.A. J. Biol. Chem. 1997; 272: 24819-24824Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar), and multiple lines of evidence suggest that they are involved in the regulation of cell adhesion and growth (6Yang W. Lin Q. Zhao J. Guan J.L. Cerione R.A. J. Biol. Chem. 2001; 276: 43987-43993Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar), receptor degradation (7Lin Q. Lo C.G. Cerione R.A. Yang W. J. Biol. Chem. 2002; 277: 10134-10138Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar), and axonal guidance (3Worby C.A. Simonson-Leff N. Clemens J.C. Huddler Jr., D. Muda M. Dixon J.E. J. Biol. Chem. 2002; 277: 9422-9428Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). ACK1 has been implicated as a mediator of epidermal growth factor signaling to Rho family GTP-binding proteins through phosphorylation and activation of guanosine exchange factors such as Dbl, suggesting a role in regulation of the cytoskeleton (8Kato J. Kaziro Y. Satoh T. Biochem. Biophys. Res. Commun. 2000; 268: 141-147Crossref PubMed Scopus (44) Google Scholar, 9Kato-Stankiewicz J. Ueda S. Kataoka T. Kaziro Y. Satoh T. Biochem. Biophys. Res. Commun. 2001; 284: 470-477Crossref PubMed Scopus (40) Google Scholar). ACK1 has also been reported to bind to adaptor proteins, suggesting that it is involved in several different signaling pathways. The SH3 domain of ACK1 binds to the proline-rich region of HSH2, an adaptor protein in hematopoietic cells, leading to its phosphorylation (10Oda T. Muramatsu M.A. Isogai T. Masuho Y. Asano S. Yamashita T. Biochem. Biophys. Res. Commun. 2001; 288: 1078-1086Crossref PubMed Scopus (24) Google Scholar), whereas the C-terminal proline-rich domain of ACK1 interacts with the adaptor proteins Nck (11Teo M. Tan L. Lim L. Manser E. J. Biol. Chem. 2001; 276: 18392-18398Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar) and Grb2 (12Satoh T. Kato J. Nishida K. Kaziro Y. FEBS Lett. 1996; 386: 230-234Crossref PubMed Scopus (50) Google Scholar), which are involved in cytoskeletal rearrangement (13Buday L. Wunderlich L. Tamas P. Cell. Signal. 2002; 14: 723-731Crossref PubMed Scopus (193) Google Scholar) and Ras activation (14Downward J. Cancer Surv. 1996; 27: 87-100PubMed Google Scholar), respectively. In addition, both DAck and ACK2 interact with the sorting nexin SH3PX1 through their C-terminal domains, leading to its phosphorylation (3Worby C.A. Simonson-Leff N. Clemens J.C. Huddler Jr., D. Muda M. Dixon J.E. J. Biol. Chem. 2002; 277: 9422-9428Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 7Lin Q. Lo C.G. Cerione R.A. Yang W. J. Biol. Chem. 2002; 277: 10134-10138Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar), and this ACK2 interaction with SH3PX1 together with clathrin promotes degradation of EGFR (7Lin Q. Lo C.G. Cerione R.A. Yang W. J. Biol. Chem. 2002; 277: 10134-10138Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar). The domain architecture of the ACK family is unique compared with other non-receptor tyrosine kinases, and ACK family members are the only tyrosine kinases known to interact with Cdc42 (15Manser E. Leung T. Salihuddin H. Tan L. Lim L. Nature. 1993; 363: 364-367Crossref PubMed Scopus (262) Google Scholar). Members of the ACK family are specific for Cdc42 and do not bind the closely related Rac and Rho GTPases (2Yang W. Cerione R.A. J. Biol. Chem. 1997; 272: 24819-24824Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar, 15Manser E. Leung T. Salihuddin H. Tan L. Lim L. Nature. 1993; 363: 364-367Crossref PubMed Scopus (262) Google Scholar). The 114-kDa human ACK1 protein consists of an N-terminal tyrosine kinase domain; an SH3 domain; and a C-terminal CRIB motif, which is required for Cdc42 binding (15Manser E. Leung T. Salihuddin H. Tan L. Lim L. Nature. 1993; 363: 364-367Crossref PubMed Scopus (262) Google Scholar). In addition, several proline-rich sequences and clathrin-binding motifs are located in the C-terminal region (11Teo M. Tan L. Lim L. Manser E. J. Biol. Chem. 2001; 276: 18392-18398Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). All ACK family members share a similar domain structure, although DAck and TNK1 do not contain the CRIB domain. PAK serine/threonine kinases also bind to Cdc42 through a CRIB motif, and this interaction promotes kinase activity (16Bokoch G.M. Annu. Rev. Biochem. 2003; 72: 743-781Crossref PubMed Scopus (885) Google Scholar). Structural studies have revealed that the molecular basis for this activation in PAK1 involves release of an intramolecular autoinhibitory module upon Cdc42 binding (17Lei M. Lu W. Meng W. Parrini M.C. Eck M.J. Mayer B.J. Harrison S.C. Cell. 2000; 102: 387-397Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar). ACK kinases appear functionally similar to PAK kinases in cell-based experiments, in which Cdc42 binding promotes ACK1 activation (8Kato J. Kaziro Y. Satoh T. Biochem. Biophys. Res. Commun. 2000; 268: 141-147Crossref PubMed Scopus (44) Google Scholar, 18Yang W. Lin Q. Guan J.L. Cerione R.A. J. Biol. Chem. 1999; 274: 8524-8530Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 19Yokoyama N. Miller W.T. J. Biol. Chem. 2003; 278: 47713-47723Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). However, as the sequence characteristics and domain organization around the CRIB motif are dissimilar in ACK and PAK1, the molecular details of ACK activation by Cdc42 are likely to be different. Additionally, unlike members of the PAK family, Cdc42 is unable to promote the activation of ACKs in vitro (2Yang W. Cerione R.A. J. Biol. Chem. 1997; 272: 24819-24824Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar, 19Yokoyama N. Miller W.T. J. Biol. Chem. 2003; 278: 47713-47723Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar), suggesting that other cellular components may be involved. The ACKs are also the only tyrosine kinases with an SH3 domain C-terminal to the kinase domain. The Src family tyrosine kinases, including Src and Hck, and the Abl tyrosine kinase have SH3 domains (located N-terminal to the kinase domain) that serve as autoinhibitory modules of the unphosphorylated kinases be activated by binding of a protein to the SH3 domain M. M. Lee J. Miller W.T. Nature. 1997; PubMed Scopus Google Scholar, M. M. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, R.A. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, M.A. K. D. W. J. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google an SH3 not increase ACK1 activity in vitro N. Miller W.T. J. Biol. Chem. 2003; 278: 47713-47723Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar), suggesting that the SH3 domain not the activity of The SH3 domain a role in protein in as in other proteins L. Biophys. 1999; PubMed Scopus Google Scholar, B.J. J. 2001; PubMed Google Scholar). the crystal structures of the ACK1 kinase domain in both the phosphorylated and unphosphorylated states. In addition to the apo complexes with both a non-hydrolyzable nucleotide analog and a general kinase inhibitor natural product have been structures an unusual conformation for the unphosphorylated of the and into both the and of of this tyrosine and ACK1 as a for a of to the kinase domain of ACK1 and to of the and to the and of the respectively. and of the by into a an N-terminal and a for and in The sequence of the by expressed this is to as The into in with and to the The to the to be used for protein in in a cell of an of of and by the to and for All The of the and a and of known to the of of The of the used for ACK1 a in in to growth in The to a of into in and the of and The the to the of a of they an of of The for of of increase in cell and for an The to in the by and and for to and in and inhibitor The by and for The to for the into a The with of of and and of in a The the of to the a of to the to a of with The in a with of with and to of and ACK1 for the and whereas the and the to the The ACK1 and into and the ACK1 by a in by of protein and of of by protein in and with a of and of to the with the protein in the growth of The by apo in a of with by in AMP-PCP, and with a of and to of in and to of the with and by in The apo in the In this apo by in and with a of and apo in the with and as and the and a crystal of and the and the a crystal of the The apo and with and Scholar) and with Biol. 1994; PubMed Scopus Google Scholar), whereas the with as in The The apo and to with whereas the to also with is crystal the and crystal and structures solved by molecular Biol. 1999; PubMed Scopus Google Scholar) J. 1997; Scopus Google Scholar) as in Biol. 1994; PubMed Scopus Google Scholar). the apo structure, a and of the C-terminal domain of the kinase domain with activation loop used as a in a all and The with a of and an of and as a in a with a of and an of The in 1996; Scholar) and The for a of unique to of of in and with by an molecular with the to of both the and C-terminal in the and of the the protein with 1997; 277: PubMed Scopus Google Scholar). The and in The and in both unable to be of N-terminal of the and the and in and in In addition, several in the activation loop and and the C-terminal in both in and in not The have been in the both the and by molecular a apo as a with all The in this seen for of in The protein by in by in All into the the the with the which by in the of of the J. 1993; Scopus Google Scholar) with as a which in a in of The and whereas the and The have been in the and for the and All with the of the of unphosphorylated that to to the The of these of and The are with a of The is with the typical protein kinase a N-terminal and a C-terminal are by a region The is by a the The N-terminal of consists of and whereas the C-terminal and and and for the cell to to to in the with a of the in the with a of the in a The closely related kinase for which a is is the EGFR kinase domain J. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). The kinase domains of ACK1 and EGFR are in and the is of are Comparison of the with and other kinase including phosphorylated H. Nature. 1996; PubMed Scopus Google Scholar), that is in an of the the reveals that the of known to be for activity to seen in kinases. the and the involved in and Additionally, the is such that the of is of the of the of an is in whereas the is in The and C-terminal of the have a different with in a conformation by is that this in conformation is the of the and the of the protein of the loop are in both The activation which activity in many protein kinases by and in to the phosphorylation Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar), is in unphosphorylated and adopts an conformation only in phosphorylated protein kinases. unusual of the activation loop appear to the conformation conformation is in contrast to several tyrosine kinases that have unphosphorylated autoinhibitory activation loop In receptor and the kinase the sequence the activation the the of the and binding L. L. Nature. 1994; PubMed Scopus Google Scholar, M. Lu Y. Y. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). In growth factor the unphosphorylated activation loop the substrate-binding M. S. M.C. Lu D. J. J. PubMed Scopus Google Scholar). In the unphosphorylated activation loop of the substrate-binding and the of the activation loop in a of to a the of nucleotide binding the of ACK1K, in the of a non-hydrolyzable analog The protein used in the a small of as by not The likely and with the of the that to and that to The of and In for a phosphorylated tyrosine in the activation loop whereas evidence of phosphorylation in is the only tyrosine in the activation loop and is the of in N. Miller W.T. J. Biol. Chem. 2003; 278: 47713-47723Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). of crystal the activation loop of that the phosphorylated activation loop is into the crystal this of small in in the In both for the and the factor for the Comparison of the of the apo and structures reveals that the and in is the and the is all in the are However, the and are different in the crystal the phosphorylation the of the structure, that the that the conformation of of phosphorylation and that are not required to bind The phosphorylated be unphosphorylated apo with a of all and the of the and C-terminal is The activation loop in the phosphorylated protein adopts a similar to that of the unphosphorylated protein for the of and rearrangement of the the is The loop not upon and only is in the for the compared with the In the structure, the nucleotide with the protein to in structures of protein kinases PubMed Scopus Google Scholar, J. 1997; PubMed Scopus Google Scholar). The and are similar in the phosphorylated and unphosphorylated although the and C-terminal of the unphosphorylated are which has the of of the the of this the of a is to the of this and that and in to a The with the of the and is the and the of in the unphosphorylated whereas these are to a in the phosphorylated are the and the protein as has been reported in protein in the analog structure, a with the J.L. Zhao H. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). also has a this the of this the and is to a with the of is that an conformation of the that a with the is not be this The are by the and the of the the of in the the and of and with the of the The other the and of and interacts with the of to protein complexes in which the loop interacts with the PubMed Scopus Google Scholar), in the the loop and with the nucleotide activation of protein kinases is in by phosphorylation of in the activation phosphorylation of to in the activation loop in a that and that for Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, Annu. Rev. Biochem. 2000; PubMed Scopus Google Scholar). In structures that the phosphorylation of and not the conformation of the We also the structures of both the phosphorylated and unphosphorylated activation to are and to the factors that the are independent in the of the unphosphorylated structure, which multiple of the activation loop In both the loop is and has a In of activation loop are in whereas the loop is in the activation loop and an of as as the of a may to the of these in not The the a of of the for in the phosphorylated the structures of the unphosphorylated activation are The the of the unphosphorylated activation in multiple the by this conformation is also in In the of the all in the phosphorylated activation loop of are in the and the activation loop of the unphosphorylated be The activation loop similar crystal with the apo activation and for an also in of this the structures of all of the unphosphorylated activation are similar in contrast to many protein kinases, closely the of the phosphorylated activation However, although the conformation of the activation loop in are in a and and several in to with the Additionally, the is for in the unphosphorylated activation loop the suggesting that it has in the phosphorylated In of these the activation loop not the substrate-binding and its conformation resembles that seen in tyrosine kinases such as the phosphorylated receptor tyrosine kinase and J. 1997; PubMed Scopus Google Scholar). the activation loop is by In ACK1K, these are loop and of the C-terminal as as loop and the of the activation these the of the the of and the of a the of the tyrosine are known tyrosine kinase activation that have been in the However, the of in is by compared with in both and phosphorylated H. Nature. 1996; PubMed Scopus Google Scholar), it in a different in the activation loop other kinases and the of this conformation in the unphosphorylated and In ACK1K, the of is to the in the of the with which the of the the of of the loop and and The of this is unique in human are in kinases. The unusual of this with the of a this in the ACK1 family its in the of the unphosphorylated loop The of this to the loop involved in with the C-terminal that it may these other known kinase of Y. H. S. S. M. T. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar) and J. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar), have an activation loop in the conformation in the unphosphorylated the activation loop tyrosine that be phosphorylated and is the activation loop by is the of the In EGFRK, the of in the activation loop has been to to the of the conformation J. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). The activation loop not have this of and is likely to be by different The of also that an the C-terminal is involved in the of the unphosphorylated activation In the structure, the of this a with an activation loop the loop the C-terminal is in ACK1K, which with the of and the activation loop the of this in of the loop of a tyrosine in its activation and of this tyrosine to of tyrosine phosphorylation in However, phosphorylation of this tyrosine in only a modest increase in activity in vitro N. Miller W.T. J. Biol. Chem. 2003; 278: 47713-47723Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). increase in activity is compared with kinases that are by their unphosphorylated activation the growth receptor kinase a increase in phosphorylated S. Miller W.T. Biol. 2001; PubMed Scopus Google Scholar). The suggest that the activation loop of ACK1 is not that phosphorylation is not for of the and that the binding of and be largely by the phosphorylation However, phosphorylation may be to an for role for activation loop phosphorylation has been for the protein kinases protein kinase and P. E. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar), in have been to in activation loop is that a similar role in has an around the activation loop and are of and of these the is in other protein kinases this phosphorylated In EGFR, which has in activity its phosphorylated tyrosine is to N. M. Y. M. Biochem. Biophys. Res. Commun. PubMed Scopus Google Scholar), many in the activation of which the activation loop tyrosine in the of the kinase domain J. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). of the the of ACK1 are not the of ACK1 a of for different of tyrosine kinases has been reported N. Miller W.T. J. Biol. Chem. 2003; 278: 47713-47723Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). Comparison of the of ACK1 with in with an to the of the reported J. 1997; PubMed Scopus Google Scholar). ACK1 has a the substrate-binding is unique in human tyrosine kinases and is in The of tyrosine kinases have this The of with the of to a that although the in is in with the the in with this and that be ACK1 activity with this and the reported for ACK1 an this N. Miller W.T. J. Biol. Chem. 2003; 278: 47713-47723Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). the reported for this is compared with for other tyrosine kinases such as Hck, which has a of its M. M. J. Miller W.T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (88) Google Scholar). The ACK1 used in the studies N. Miller W.T. J. Biol. Chem. 2003; 278: 47713-47723Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar) the SH3 and addition of an SH3 not serve to increase the activity in Additionally, the domain also an in the of Cdc42 N. Miller W.T. J. Biol. Chem. 2003; 278: 47713-47723Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). Furthermore, have also only of phosphorylation of compared with other and of a of known tyrosine kinase phosphorylation only phosphorylated not these suggest that the of ACK1 is in both the phosphorylated and unphosphorylated that the sequence and of for ACK1 to be of to an has been implicated in Cdc42 to the in Y. M.A. P. Manser E. S. Biochem. Biophys. Res. Commun. PubMed Scopus Google Scholar) and may be a for the of a in a of to a small solved the of to to of apo protein that in the is a natural product in and has been to many protein kinases in an L. M. M. J. J. Chem. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The the of and binds in a similar to that in a with L. M. M. J. J. Chem. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). In contrast to the nucleotide the of the inhibitor a ordering of the In the the loop is and with the it The and and the inhibitor binds in In the inhibitor with the protein and a of All of the interact with of the which its to many protein kinases. are with the of and is the of the and the The of the a with the of in the by the of for to the and is of the motif that the activation The also a with the of in the loop in not and likely to the of this In the loop is not in as and of a a the loop and the is a multidomain non-receptor tyrosine kinase that has only a modest increase in activity upon phosphorylation in vitro N. Miller W.T. J. Biol. Chem. 2003; 278: 47713-47723Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). We have solved the structures of both the phosphorylated and unphosphorylated of and that they are of the activation loop is not required to the activation loop and the in an in the activation loop appear to the conformation in the of phosphorylation. In an in the activation loop the loop and in typical phosphorylated activation also appear to the unphosphorylated activation loop studies that the tyrosine in ACK1 is in N. Miller W.T. J. Biol. Chem. 2003; 278: 47713-47723Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar), phosphorylation of this tyrosine not appear to have an the of the activation We have also solved the of with nucleotide and this that rearrangement of the kinase domain is not to bind In addition to these of the region in reveals that the of in this region may ACK1 not many to other tyrosine kinases N. Miller W.T. J. Biol. Chem. 2003; 278: 47713-47723Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). The unique domain of together with the conformation of the unphosphorylated kinase domain and the unusual substrate-binding that the and of in may be of other tyrosine kinases. We the and the and for the and of for ACK1 kinase and for in the protein and and for of this
No takes yet. Share an insight, caveat, or question.
Lougheed et al. (2004) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: